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Paper 1 Date: June 5, 2015 332129-v4/4548-01200 UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD COALITION FOR AFFORDABLE DRUGS VII LLC, Petitioner, v. POZEN INC., Patent Owner. IPR2015-01344 Patent 8,858,996 PETITION FOR INTER PARTES REVIEW

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Paper 1 Date: June 5, 2015

332129-v4/4548-01200

UNITED STATES PATENT AND TRADEMARK OFFICE

BEFORE THE PATENT TRIAL AND APPEAL BOARD

COALITION FOR AFFORDABLE DRUGS VII LLC, Petitioner,

v.

POZEN INC., Patent Owner.

IPR2015-01344 Patent 8,858,996

PETITION FOR INTER PARTES REVIEW

IPR2015-01344 Patent 8,858,996

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TABLE OF CONTENTS

I.  Introduction .................................................................................................... 1 

II.  Mandatory Notices Per 37 C.F.R. § 42.8 ..................................................... 1 

A.  Real Party-In-Interest ............................................................................ 1 

B.  Notice of Related Matters ..................................................................... 2 

C.  Lead and Back-Up Counsel and Service Information .......................... 3 

III.  Payment of Fees ............................................................................................. 4 

IV.  Requirements Per 37 C.F.R. § 42.104 .......................................................... 4 

A.  Grounds for Standing ............................................................................ 4 

B.  Identification of Challenge and Precise Relief Requested .................... 4 

C.  Evidence Relied Upon to Support the Challenge .................................. 5 

D.  The Grounds Are Not Redundant or Duplicative ................................. 5 

V.  Background .................................................................................................... 6 

A.  State of the Art ...................................................................................... 6 

B.  Prosecution History of the ’996 Patent ................................................. 8 

C.  Person of Ordinary Skill in the Art (POSA) ......................................... 9 

VI.  Claim Construction ....................................................................................... 9 

A.  “inhibited/inhibits” ................................................................................ 9 

B.  All Remaining Terms .......................................................................... 11 

VII.  Ground 1: Goldman in view of Remington in further view of Lindberg Renders Obvious Claims 1-19 ................................................... 11 

A.  A POSA Would Have Combined Goldman, Remington, and Lindberg .............................................................................................. 11 

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B.  Claim 1: ............................................................................................... 13 

1.  A pharmaceutical composition in unit dosage form in the form of a tablet, said composition comprising: ........................ 13 

2.  naproxen in an amount of 200-600 mg per unit dosage form; and ................................................................................... 13 

3.  esomeprazole in an amount of from 5 to 100 mg per unit dosage form, .............................................................................. 14 

4.  wherein upon introduction of said unit dosage form into a medium, at least a portion of said esomeprazole is released regardless of the pH of the medium, and .................... 14 

5.  release of at least a portion of said naproxen is inhibited unless the pH of said medium is 3.5 or higher. ........................ 16 

C.  Claim 2: The pharmaceutical composition of claim 1, wherein ......... 16 

1.  said naproxen is present in a core layer, ................................... 17 

2.  wherein said core layer has a coating that inhibits its release from said unit dosage form unless said dosage form is in a medium with a pH of 3.5 or higher. ...................... 17 

D.  Claim 3: The pharmaceutical composition of claim 1, wherein said unit dosage form is a multilayer tablet comprising a core layer and one or more layers outside of said core layer. ..................... 17 

E.  Claim 4: The pharmaceutical composition of claim 3, wherein said core layer comprises naproxen. ................................................... 18 

F.  Claim 5: The pharmaceutical composition of claim 3, wherein at least one of said one more layers outside said core layer comprises esomeprazole. ..................................................................... 18 

G.  Claim 6: The pharmaceutical composition of claim 3, wherein said one or more layers outside of said core layer do not contain naproxen. ............................................................................................. 19 

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H.  Claim 7: The pharmaceutical composition of claim 1, further comprising at least one carrier. ........................................................... 19 

I.  Claim 8: The pharmaceutical composition of claim 1, further comprising at least one auxiliary agent chosen from the group consisting of lubricants, preservatives, disintegrants, stabilizers, wetting agents, emulsifiers, salts, buffers, coloring agents, flavoring agents, and aromatic substances. ......................................... 20 

J.  Claim 9: The pharmaceutical composition of claim 1, further comprising at least one ingredient to adjust pH. ................................. 20 

K.  Claim 10: A method of treating a patient for pain or inflammation, comprising administering to said patient the pharmaceutical composition of claim 1. ............................................. 21 

L.  Claim 11: The method of claim 10, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis. ................................................................................................ 21 

M.  Claim 12: ............................................................................................. 21 

1.  A pharmaceutical composition in unit dosage form in the form of a tablet, said composition comprising: ........................ 21 

2.  a core layer comprising naproxen, wherein .............................. 22 

3.  said core layer has a coating that inhibits release of said naproxen from said core layer unless said dosage form is in a medium with a pH of 3.5 or higher; and ............................ 23 

4.  a layer comprising esomeprazole, wherein ............................... 23 

5.  said layer has a non-enteric film coating that, upon ingestion by a patient, releases said esomeprazole into the stomach of said patient. ............................................................. 24 

N.  Claim 13: The pharmaceutical composition of claim 12, wherein naproxen is present in said unit dosage form in an amount of 200-600 mg. ....................................................................... 25 

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O.  Claim 14: The pharmaceutical composition of claim 12, wherein esomeprazole is present in said unit dosage form in an amount of from 5 to 100 mg. ............................................................... 26 

P.  Claim 15: The pharmaceutical composition of claim 12, wherein ................................................................................................ 26 

1.  naproxen is present in said unit dosage form in an amount of between 200-600 mg and ......................................... 26 

2.  esomeprazole in an amount of from 5 to 100 mg per unit dosage form. .............................................................................. 26 

Q.  Claim 16: A method of treating a patient for pain or inflammation, comprising administering to said patient the pharmaceutical composition of claim 12. ........................................... 27 

R.  Claim 17: The method of claim 16, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis. ................................................................................................ 27 

S.  Claim 18: A method of treating a patient for pain or inflammation, comprising administering to said patient the pharmaceutical composition of claim 15. ........................................... 27 

T.  Claim 19: The method of claim 18, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis. ................................................................................................ 28 

VIII.  Ground 2: Gimet in view of Goldman and Lindberg Renders Obvious Claims 1-19 .................................................................................... 28 

A.  A POSA Would Have Combined Gimet, Goldman, and Lindberg .............................................................................................. 28 

B.  Claim 1: ............................................................................................... 31 

1.  A pharmaceutical composition in unit dosage form in the form of a tablet, said composition comprising: ........................ 31 

2.  naproxen in an amount of 200-600 mg per unit dosage

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form; and ................................................................................... 31 

3.  esomeprazole in an amount of from 5 to 100 mg per unit dosage form, .............................................................................. 32 

4.  wherein upon introduction of said unit dosage form into a medium, at least a portion of said esomeprazole is released regardless of the pH of the medium, and .................... 33 

5.  release of at least a portion of said naproxen is inhibited unless the pH of said medium is 3.5 or higher. ........................ 34 

C.  Claim 2: The pharmaceutical composition of claim 1, wherein ......... 35 

1.  said naproxen is present in a core layer, ................................... 35 

2.  wherein said core layer has a coating that inhibits its release from said unit dosage form unless said dosage form is in a medium with a pH of 3.5 or higher. ...................... 35 

D.  Claim 3: The pharmaceutical composition of claim 1, wherein said unit dosage form is a multilayer tablet comprising a core layer and one or more layers outside of said core layer. ..................... 36 

E.  Claim 4: The pharmaceutical composition of claim 3, wherein said core layer comprises naproxen. ................................................... 36 

F.  Claim 5: The pharmaceutical composition of claim 3, wherein at least one of said one more layers outside said core layer comprises esomeprazole. ..................................................................... 37 

G.  Claim 6: The pharmaceutical composition of claim 3, wherein said one or more layers outside of said core layer do not contain naproxen. ............................................................................................. 37 

H.  Claim 7: The pharmaceutical composition of claim 1, further comprising at least one carrier. ........................................................... 38 

I.  Claim 8: The pharmaceutical composition of claim 1, further comprising at least one auxiliary agent chosen from the group consisting of lubricants, preservatives, disintegrants, stabilizers,

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wetting agents, emulsifiers, salts, buffers, coloring agents, flavoring agents, and aromatic substances. ......................................... 38 

J.  Claim 9: The pharmaceutical composition of claim 1, further comprising at least one ingredient to adjust pH. ................................. 39 

K.  Claim 10: A method of treating a patient for pain or inflammation, comprising administering to said patient the pharmaceutical composition of claim 1. ............................................. 40 

L.  Claim 11: The method of claim 10, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis. ................................................................................................ 40 

M.  Claim 12: ............................................................................................. 40 

1.  A pharmaceutical composition in unit dosage form in the form of a tablet, said composition comprising: ........................ 40 

2.  a core layer comprising naproxen, wherein .............................. 41 

3.  said core layer has a coating that inhibits release of said naproxen from said core layer unless said dosage form is in a medium with a pH of 3.5 or higher; and ............................ 41 

4.  a layer comprising esomeprazole, wherein ............................... 42 

5.  said layer has a non-enteric film coating that, upon ingestion by a patient, releases said esomeprazole into the stomach of said patient. ............................................................. 43 

N.  Claim 13: The pharmaceutical composition of claim 12, wherein naproxen is present in said unit dosage form in an amount of 200-600 mg. ....................................................................... 44 

O.  Claim 14: The pharmaceutical composition of claim 12, wherein esomeprazole is present in said unit dosage form in an amount of from 5 to 100 mg. ............................................................... 45 

P.  Claim 15: The pharmaceutical composition of claim 12, wherein ................................................................................................ 45 

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1.  naproxen is present in said unit dosage form in an amount of between 200-600 mg and ......................................... 45 

2.  esomeprazole in an amount of from 5 to 100 mg per unit dosage form. .............................................................................. 46 

Q.  Claim 16: A method of treating a patient for pain or inflammation, comprising administering to said patient the pharmaceutical composition of claim 12. ........................................... 46 

R.  Claim 17: The method of claim 16, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis. ................................................................................................ 46 

S.  Claim 18: A method of treating a patient for pain or inflammation, comprising administering to said patient the pharmaceutical composition of claim 15. ........................................... 47 

T.  Claim 19: The method of claim 18, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis. ................................................................................................ 47 

IX.  Ground 3: The Plachetka ’255 Publication Anticipates Claims 1-19 ................................................................................................................... 47 

A.  The Earliest Effective Filing Date of the ’996 Patent is May 16, 2005 Due to a Break in Priority ............................................ 47 

B.  The Plachetka ’255 Publication Discloses Each Limitation of Claims 1-19 ......................................................................................... 52 

X.  Any Secondary Considerations of Nonobviousness Would Fail ............. 60 

XI.  Conclusion .................................................................................................... 60 

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TABLE OF AUTHORITIES

Cases 

Chester v. Miller, 906 F.2d 1574 (Fed. Cir. 1990)............................................................................ 52

Iron Dome LLC v. Chinook Licensing DE LLC, IPR2014-00674, Paper 9 (Sept. 10, 2004) ............................................................. 4

Statutes 

35 U.S.C. § 102(b) .............................................................................................. 5, 48

35 U.S.C. § 103(a) .................................................................................................4, 5

35 U.S.C. § 311(a) ..................................................................................................... 4

35 U.S.C. §§ 311-319 ................................................................................................ 1

Regulations 

37 C.F.R. § 42.10(b) .................................................................................................. 3

37 C.F.R. § 42.100 et seq. .......................................................................................... 1

37 C.F.R. § 42.104 ..................................................................................................... 4

37 C.F.R. § 42.15(a) ................................................................................................... 4

37 C.F.R. § 42.6(c) ..................................................................................................... 5

37 C.F.R. § 42.63(e) ................................................................................................... 5

37 C.F.R. § 42.8 ......................................................................................................... 1

37 C.F.R. § 42.8(b)(1) ................................................................................................ 1

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37 C.F.R. § 42.8(b)(2) ................................................................................................ 2

37 C.F.R. § 42.8(b)(3) ................................................................................................ 3

37 C.F.R. § 42.8(b)(4) ................................................................................................ 3

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EXHIBIT LIST

Exhibit No. Description

1001 U.S. Patent No. 8,858,996 (“the ’996 Patent”)

1002 File History of the ’996 Patent, U.S. Patent App. No. 14/244,471 (“the ’471 Application”)

1003 Declaration of Leon Shargel, Ph.D., R.Ph.

1004 U.S. Patent No. 5,204,118 (“Goldman”)

1005 “Remington’s Pharmaceutical Sciences,” Alfonso R. Gennaro, et al., Mack Publ’g Co., Seventeenth Edition, 1985 (“Remington”)

1006 U.S. Patent No. 5,698,225 (“Gimet”)

1007 U.S. Patent No. 5,714,504 (“Lindberg”)

1008 U.S. Patent App. Pub. No. US 2003/0069255 (“the ’255 Plachetka Publication”)

1009 U.S. Patent Prov. App. No. 60/294,588 (“the ’588 Application”)

1010 U.S. Patent App. No. 10/158,216 (“the ’216 Application”)

1011 U.S. Patent App. No. 11/129,320 (“the ’320 Application”)

1012 U.S. Patent No. 4,757,060

1013 “The Mechanism of Action of Aspirin,” J.R. Vane, et al., Pergamon (2003)

1014 G.B. Patent No. 1211134

1015 “Drug-Induced Peptic Ulcer Disease,” Valerie Vella, Journal of the Malta College of Pharmacy Practice (2005)

IPR2015-01344 Patent 8,858,996

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Exhibit No. Description

1016 “Goodman & Gilman’s The Pharmacological Basis of Therapeutics,” Joel G. Hardman, et al., McGraw-Hill Publ’g Co., Ninth Edition (1996)

1017 “Upper Gastrointestinal (GI) pH in Young, Healthy Men and Women,” Jennifer B. Dressman, et al., Pharmaceutical Research, Vol. 7, No. 7, 756-761 (1990)

1018 “Effect of Orally Administered Prostaglandin E2 and its 15-Methyl Analogues on Gastric Secretion,” Karim, et al., British Med. Journal (Jan. 20, 1973)

1019 “Tagamet: The Discovery of Histamine H2-Receptor Antagonists,” SmithKlein Beecham Pharmas., Am. Chem. Soc. (Nov. 24, 1997)

1020 “Inhibition of Gastric (H+ + K+)-ATPase by the Substituted Benzimidazole Picoprazole,” B. Wallmark, et al., Biochimica et Biophysica Acta, Vol. 728, at 31-38 (1983)

1021 U.S. Patent No. 4,255,431

1022 Notice of Final Determination, In re: Patent Term Extension for U.S. Patent No. 6,143,771

1023 “Drug Discovery: Practices, Processes, and Perspectives,” Jie Jack Li, et al., John Wiley & Sons (Apr. 3, 2013)

1024 “Prevention of the Gastrointestinal Adverse Effects of Nonsteroidal Anti-Inflammatory Drugs, Gregor J.E. Brown, et al., Drug Safety (6): 503-512 (December 21, 1999)

1025 U.S. Patent App. Pub. 2002/0045184 (“Chen”)

1026 “Management of NSAID-Related Gastrointestinal Mucosal Injury,” A.F. Barrison, et al., Inflammopharmacology 7(3), at 277-86 (1999)

1027 “Prevention of NSAID-Induced Gastroduodenal Ulcers,” A. Rostom, et al., Cochrane Database of Systematic Reviews (2000)

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Exhibit No. Description

1028 “Abolition by Omeprazole of Aspirin Induced Gastric Mucosal Injury in Man,” T K Daneshmend et al., Gut, Vol. 31, 514-517 (1990) (“Daneshmend”)

1029 U.S. Patent No. 6,319,519

1030 U.S. Patent No. 6,365,184 (“Depui”)

1031 VIMOVO® (Naproxen and Esomeprazole Magnesium) Tablets | Horizon Pharma, http://www.horizonpharma.com/vimovo/ (last visited May 9, 2015)

1032 Horizon Pharma plc 2014 Irish Statutory Accounts,” Horizon Pharma Public Limited Company (Apr. 9, 2015)

1033 Shargel Walmart Receipts

1034 April 4, 2014 Patent Owner Responses to Invalidity Contentions

1035 Inhibit, http://www.merriam-webster.com/dictionary/inhibit (last visited Feb. 17, 2015)

1036 Organic Chemistry, Robert Thornton Morrison, Sixth Edition, 1992

1037 The Random House Dictionary of the English Language, Random House, First Printing, 1966

1038 The Oxford Encyclopedic English Dictionary, Joyce M. Hawkins, et al., 1991

1039 WO 98/54171

1040 U.S. Patent No. 6,262,085

1041 U.S. Patent Pub. No. 2001/0000468

1042 U.S. Patent No. 5,051,262

1043 U.S. Patent No. 5,314,697

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Exhibit No. Description

1044 “Effects of Misoprostol on Gastric Acid and Mucus Secretion in Man,” Donald E. Wilson, et al., Digestive Diseases and Sciences, Vol. 31, No. 2, Feb. 1986.

1045 “Measurement of Gastrointestinal pH Profiles in Normal Ambulant Human Subjects,” D. F. Evans, et al., Gut, Vol. 29, 1035-1041 (1988) (“Evans”)

1046 Prevent, http://www.merriam-webster.com/dictionary/prevent (last visited June 4, 2015)

1047 “Omeprazole,” Stephen P. Clissold, et al., Drugs, vol. 32 (1986) (“Clissold”)

1048 “Development of an Oral Formulation of Omeprazole,” Pilbrant and Cederberg, Scand. J. Gastroenterol., 20(Suppl. 108):113-120 (1985) (“Pilbrant”)

1049 “Effects of Single and Repeated Doses of Omeprazole in Gastric Acid and Pepsin Secretion in Man,” Howden et al., Gut, Vol. 25, 707-710 (1984) (“Howden”)

1050 “Omeprazole: A Study of Its Inhibition of Gastric pH and Oral Pharmacokinetics After Morning or Evening Dosage,” Prichard et al., Gastroenterol., 88:64-69 (1985) (“Prichard”)

1051 “The Effects of Oral Doses of Lansoprazole and Omeprazole on Gastric pH,” Tolman et al., J. Clin. Gastroenterol, 24(2):65-70 (1997) (“Tolman”)

1052 Citizen Petition, Horizon Pharma (February 4, 2014)

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Exhibit No. Description

1053 “Clinical Trial: Evaluation of Gastric Acid Suppression with Three Doses of Immediate-Release Esomeprazole in the Fixed-Dose Combination of PN 400 (Naproxen/Esomeprazole Magnesium) Compared with Naproxen 500 mg and Enteric-Coated Esomeprazole 20 mg: A Randomized, Open-Label, Phase I Study in Healthy Volunteers,” Miner et al., Alim. Pharmacol. Ther., 32:414-424 (2010) (“Miner”)

1054 FDA Response to Horizon’s Citizen Petition (July 3, 2014)

IPR2015-01344 Patent 8,858,996

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I. Introduction

The Coalition for Affordable Drugs VII LLC (“CFAD” or “Petitioner”)

respectfully requests inter partes review of claims 1-19 of U.S. Patent No.

8,858,996 (“the ’996 Patent”) (Ex. 1001) in accordance with 35 U.S.C. §§ 311-319

and 37 C.F.R. § 42.100 et seq. The ’996 Patent is assigned to Pozen Inc.

II. Mandatory Notices Per 37 C.F.R. § 42.8

A. Real Party-In-Interest

Pursuant to 37 C.F.R. § 42.8(b)(1), CFAD certifies that Coalition For

Affordable Drugs VII LLC; Hayman Credes Master Fund, L.P. (“Credes”);

Hayman Orange Fund SPC – Portfolio A (“HOF”); Hayman Capital Master Fund,

L.P. (“HCMF”); Hayman Capital Management, L.P. (“HCM”); Hayman Offshore

Management, Inc. (“HOM”); Hayman Investments, L.L.C. (“HI”); nXn Partners,

LLC (“nXnP”); IP Navigation Group, LLC (“IPNav”); J Kyle Bass; and Erich

Spangenberg (collectively, “RPI”) are the real parties-in-interest. The RPI certify

the following: CFAD is a wholly owned subsidiary of Credes. Credes is a limited

partnership. HOF is a segregated portfolio company. HCMF is a limited

partnership. HCM is the general partner and investment manager of Credes and

HCMF. HCM is the investment manager of HOF. HOM is the administrative

general partner of Credes and HCMF. HI is the general partner of HCM. J Kyle

Bass is the sole member of HI and sole shareholder of HOM. CFAD, Credes,

IPR2015-01344 Patent 8,858,996

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HOF, and HCMF act, directly or indirectly, through HCM as the general partner

and/or investment manager of Credes, HOF, and HCMF. nXnP is a paid

consultant to HCM. Erich Spangenberg is the Manager and majority member of

nXnP. IPNav is a paid consultant to nXnP. Erich Spangenberg is the Manager and

majority member of IPNav. Other than HCM and J Kyle Bass in his capacity as

the Chief Investment Officer of HCM and nXnP and Erich Spangenberg in his

capacity as the Manager/CEO of nXnP, no other person (including any investor,

limited partner, or member or any other person in any of CFAD, Credes, HOF,

HCMF, HCM, HOM, HI, nXnP, or IPNav) has authority to direct or control (i) the

timing of, filing of, content of, or any decisions or other activities relating to this

petition or (ii) any timing, future filings, content of, or any decisions or other

activities relating to the future proceedings related to this petition. All of the costs

associated with this petition are expected to be borne by HCM, CFAD, Credes,

HOF, and/or HCMF.

B. Notice of Related Matters

Per 37 C.F.R. § 42.8(b)(2), CFAD is aware of the following judicial matters

involving the ’996 Patent: (1) Horizon Pharma, Inc. v. Actavis Labs. FL, Inc.,

3:15-cv-03322 (D.N.J.); (2) Horizon Pharma, Inc. v. Dr. Reddy’s Labs., Inc., 3:15-

cv-03324 (D.N.J.); (3) Horizon Pharma, Inc. v. Lupin Ltd., 3:15-cv-03326

(D.N.J.); and (4) Horizon Pharma, Inc., v. Mylan Pharmas., Inc. 3:15-cv-03327

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(D.N.J.). In addition, CFAD is aware of the following judicial and administrative

matters involving patents related to the ’996 Patent: (1) AstraZeneca AB v. Dr.

Reddy’s Labs. Inc., 3:11-cv-02317 (D.N.J.); (2) AstraZeneca AB v. Dr. Reddy’s

Labs., Inc., 3:13-cv-00091 (D.N.J.); (3) AstraZeneca AB v. Watson Labs., Inc.-

Florida, 3:13-cv-03038 (D.N.J.); (4) AstraZeneca AB v. Mylan Pharmas., 3:13-cv-

04022 (D.N.J.); (5) Dr. Reddy’s Labs., Inc. v. Pozen Inc., IPR2015-00802

(P.T.A.B.); and Coalition for Affordable Drugs VII LLC v. Pozen Inc., IPR2015-

01241 (P.T.A.B.).

C. Lead and Back-Up Counsel and Service Information

Per 37 C.F.R. § 42.8(b)(3), CFAD designates counsel as follows:

Lead Counsel Back-Up Counsel Amy E. LaValle (Reg. No. 51,092) [email protected] Postal and Hand-Delivery Address: Conley Rose, P.C. 5601 Granite Parkway, Suite 500 Plano, Texas 75024 (972) 731-2288 (phone) (972) 731-2289 (fax)

Jerry C. Harris, Jr. (Reg. No. 66,822) [email protected] Rodney B. Carroll (Reg. No. 39,624) [email protected] Postal and Hand-Delivery Address: Conley Rose, P.C. 5601 Granite Parkway, Suite 500 Plano, Texas 75024 (972) 731-2288 (phone) (972) 731-2289 (fax)

Per 37 C.F.R. § 42.8(b)(4), CFAD may be served at the above addresses for Lead

and Back-Up Counsel. CFAD consents to electronic service by e-mail. Per 37

C.F.R. § 42.10(b), a Power of Attorney accompanies this Petition.

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III. Payment of Fees

The undersigned authorizes the Office to charge the fee required by

37 C.F.R. § 42.15(a) for this Petition to Deposit Account No. 50-1515.

IV. Requirements Per 37 C.F.R. § 42.104

A. Grounds for Standing

CFAD certifies that the ’996 Patent is available for inter partes review and

that CFAD is not barred or estopped from requesting inter partes review

challenging claims 1-19 of the ’996 Patent on the grounds identified in this

Petition. Pursuant to 35 U.S.C. § 311(a), any person or entity, including CFAD,

“who is not the owner of a patent may file with the Office a petition to institute an

inter partes review of the patent.” See Iron Dome LLC v. Chinook Licensing DE

LLC, IPR2014-00674, Paper 9 (Sept. 10, 2004) (allowing petition filed by third

party with no relationship to any parties to lawsuits involving patent owner to

proceed on the merits). Accordingly, CFAD has standing and is entitled to petition

the PTAB for review of the ’996 Patent.

B. Identification of Challenge and Precise Relief Requested

Ground 1: CFAD challenges claims 1-19 of the ’996 Patent and seeks a

ruling that those claims are unpatentable under 35 U.S.C. § 103(a) as obvious over

Goldman (Ex. 1004) in view Remington (Ex. 1005) and in further view of

Lindberg (Ex. 1007). Goldman, Remington, and Lindberg are available as prior art

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under 35 U.S.C. § 102(b).

Ground 2: CFAD challenges claims 1-19 of the ’996 Patent and seeks a

ruling that those claims are unpatentable under 35 U.S.C. § 103(a) as obvious over

Gimet (Ex. 1006) in view of Goldman (Ex. 1004) and in further view of Lindberg

(Ex. 1007). Gimet, Goldman, and Lindberg are available as prior art under 35

U.S.C. § 102(b).

Ground 3: CFAD challenges claims 1-19 of the ’996 Patent and seeks a

ruling that those claims are unpatentable under 35 U.S.C. § 102(b) as anticipated

by the Plachetka ’255 Publication (Ex. 1008). As discussed in detail below in

Section IX, the Plachetka ’255 Publication is available as prior art under 35 U.S.C.

§ 102(b) because it published on April 10, 2003, more than one year prior to the

earliest effective filing date of the ’996 Patent.

C. Evidence Relied Upon to Support the Challenge

CFAD relies upon the publications cited herein in support of Grounds 1-3.

CFAD also relies upon the Declaration of Leon Shargel, Ph.D., R.Ph. (Ex. 1003)

and the documents cited therein. Filed herewith are an Exhibit List and copies of

the references per 37 C.F.R. § 42.63(e) and 37 C.F.R. § 42.6(c).

D. The Grounds Are Not Redundant or Duplicative

The instant Petition is an original challenge to the ’996 Patent, contains only

three non-redundant grounds, and provides a detailed element-by-element analysis

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that is supported by explanation and evidence, including expert testimony.

Grounds 1 and 2 are obviousness grounds based on different primary references,

and Ground 3 is based on a single reference that is not included in Grounds 1 or 2.

As such, CFAD is entitled to have this challenge to the ’996 Patent fully

considered on the merits because the three unpatentability grounds presented in

this Petition are not redundant, duplicative, or improper in any way.

V. Background

A. State of the Art

Non-steroidal anti-inflammatory drugs (NSAIDs) refer to a group of drugs

that reduce pain, inflammation, and fever. (Ex. 1003, ¶ 30.) Aspirin is one type of

NSAID. (Id.) Bayer first chemically synthesized aspirin in the 1890s and began

selling aspirin in 1899. (Id.) Syntex Corporation disclosed its synthesis of the

NSAID, naproxen, in 1968. (Id.) Since at least 1971, NSAIDs like aspirin and

naproxen have been known to increase gastric acid production and, thus, increase

the incidence of gastric ulcers. (Id.)

Acid inhibitors refer to a group of agents that reduce gastric acid secretion

and gastric acidity. (Ex. 1003, ¶ 31.) Prostaglandins and proton pump inhibitors

(PPIs) are types of acid inhibitors. (Id. at 32.) In 1996, misoprostol, a

prostaglandin, was known to inhibit gastric acid secretion and was approved for the

treatment of gastric ulcer disease induced by NSAIDs. (Id.) Omeprazole, a PPI,

IPR2015-01344 Patent 8,858,996

7

and its inhibition of gastric action production, was discovered in the early 1980s.

(Id.) In 1987, a group led by Gunnel Sundén separated the PPI, esomeprazole,

which is the enantiopure (S)-isomer of omeprazole, with improved purity and

stability. (Id.; see also Ex. 1007, col. 3 ll. 48-55.)

Although NSAIDs provide certain therapeutic benefits, their tendency to

increase the incidence of gastric ulcers may limit their use. (Ex. 1003, ¶ 34.) In

order to avoid such limitations, NSAIDs have been used with acid inhibitors at

least as early as 1986. (Id.) For decades before that time, doctors had

recommended that patients take over-the-counter gastric acid neutralizers like

Maalox® along with NSAIDs. (Id.) Moreover, acid inhibitors have been combined

with NSAIDs in a single tablet (i.e., a combination therapy) at least as early as

1986. (Ex. 1003, ¶ 36.) For example, U.S. Patent No. 6,365,184 discloses a single

tablet comprising both an NSAID and an acid inhibitor. (Id.)

Vimovo® is a combination therapy of naproxen and esomeprazole

magnesium. (Ex. 1003, ¶ 39.) Vimovo’s® ingredients, naproxen and

esomeprazole magnesium, are available separately as generic drug products. (Id.)

Pozen’s affiliates, including Horizon Pharma USA (“Horizon”) and AstraZeneca

AB (“AstraZeneca”), currently market and sell Vimovo®. Horizon admits that the

active pharmaceutical ingredients (APIs) in Vimovo® “have been on the market . . .

for many years.” (Horizon Pharma plc 2014 Irish Statutory Accounts (Ex. 1032) at

IPR2015-01344 Patent 8,858,996

8

35.) For this reason, Horizon resorts to sales tactics to convince physicians to

prescribe—and pharmacists to dispense—Vimovo®. (Ex. 1032 at 5.)

Horizon admits that sales of Vimovo® may suffer “[i]f we are unsuccessful

in convincing physicians to complete prescriptions through our PME program or

otherwise provide prescribing instructions prohibiting the substitution of . . .

generic naproxen and branded Nexium® (esomeprazole) as a substitute.” (Ex.

1032, at 17 (emphasis added).) This is a common strategy when APIs are not

themselves patent worthy. (Ex. 1003, ¶ 40.) Nonetheless, by virtue of obtaining

the ’996 Patent, Pozen and its affiliates have succeeded, thus far, in extending a

monopoly on a long-known combination that should be available to the public.

(Id.)

The rewards for such an extension are considerable. Currently, Vimovo®

can be purchased for $26.46 per tablet. (Ex. 1003, ¶ 41.) In contrast, a similar

dosage of the two APIs of Vimovo®—esomeprazole magnesium and naproxen—

can be purchased without a prescription for under $1.00 total. (Id.) In other

words, for the same APIs, the public must pay 30-40 times more for Vimovo®.

B. Prosecution History of the ’996 Patent

The ’996 Patent was not substantively examined. The examiner did not

make any rejections to the claims based on the prior art references that support the

Grounds in this Petition. (Ex. 1002.) In fact, the application proceeded directly to

IPR2015-01344 Patent 8,858,996

9

allowance without any office actions. (Id.) Although the references included in

this petition, or similar disclosures thereof, are listed as “References Cited” on the

face of the ’996 Patent, they are buried among hundreds of other cited references.

(Id.)

C. Person of Ordinary Skill in the Art (POSA)

The field of the ’996 Patent is pharmacology. (Ex. 1003, ¶¶ 53.) A POSA

in that field at the time of the alleged invention of the ’996 Patent, presumably

June 1, 2001, would have been a pharmacist, medical doctor, or pharmaceutical

scientist having a doctor of medicine degree, a doctor of pharmacy degree, or a

Ph.D. degree, or equivalent training or degree, and at least two years of practical

experience or clinical research in pharmaceutical formulations. (Id.)

Alternatively, a POSA at the time of the alleged invention would have been a

pharmacologist or pharmacokineticist having a Ph.D. degree or equivalent training

or degree and at least two years of practical experience or clinical research in

pharmacology or pharmacokinetics. (Id.)

VI. Claim Construction

A. “inhibited/inhibits”

Claim 1 includes the term “inhibited” and claims 2 and 12 include the term

“inhibits” to refer to the release of naproxen. (Ex. 1001, col. 21 ll. 34, 38; col. 22 l.

21.) Although the words “inhibit” and “inhibitor” appear frequently throughout the

IPR2015-01344 Patent 8,858,996

10

specification of the ’996 Patent, never once does the ’996 Patent specification use

either of these words to characterize the release of an NSAID. Instead, these

words are used in the ’996 Patent specification to describe the biochemical

mechanism of action of acid inhibitors. (See, e.g., Ex. 1001, col. 3 ll. 38-40 (“The

term “acid inhibitor” refers to agents that inhibit gastric acid secretion and increase

gastric pH.”).) This has nothing to do with the release of naproxen.

Because the ’996 Patent specification neither uses “inhibit” in any way other

than its plain and ordinary meaning, nor assigns it any different meaning to

describe the release of an NSAID, its ordinary meaning should apply. Indeed, in

litigation involving related patents, Pozen argued that plain and ordinary meaning

should apply to the term “inhibit” and cited a dictionary definition to support its

construction: “to prevent or slow down the activity or occurrence of (something).”

(Ex. 1034 at 51; Ex. 1035 (www.merriamwebster.com/dictionary/inhibit).) Other

dictionaries are consistent in defining “inhibit,” “inhibitor,” and “inhibition” to

include “slow down,” “hinder,” or “prevent.” (Ex. 1036-1038). Thus, the broadest

reasonable interpretation of “inhibit” in light of the specification of the ’996 Patent

is “to slow down, hinder, or prevent.” Accordingly, the broadest reasonable

interpretation of “inhibited” is “slowed down, hindered, or prevented.” (Ex. 1003,

¶ 57.)

The meaning of “inhibit” is broader than the meaning of “prevent.”

IPR2015-01344 Patent 8,858,996

11

“Prevent” means “to stop.” (Ex. 1046; Ex. 1003, ¶ 58.) Accordingly, the meaning

of “inhibited” is broader than the meaning of “prevented.” “Prevented” means

“stopped.” (Id.)

B. All Remaining Terms

Per 37 C.F.R. § 42.100(b), all remaining terms in claims 1-19 should “be

given [their] broadest reasonable construction in light of the specification.”

VII. Ground 1: Goldman in view of Remington in further view of Lindberg Renders Obvious Claims 1-19

A. A POSA Would Have Combined Goldman, Remington, and Lindberg

A POSA faced with a common task such as manufacturing a combination

therapy oral dosage form comprising known ingredients would have had a

rationale (e.g., motivation) and a reasonable expectation of success in consulting

one or more reputable publications providing conventional techniques and

compositions to perform the task. (Ex. 1003, ¶ 88.) Goldman provides a POSA

with a rationale, e.g., a specific teaching, suggestion and motivation, to look to

conventional techniques for preparing medicament tablets as set forth in

Remington and further incorporates by reference the disclosure of Remington. (Ex.

1005, col. 6 ll. 26-33; Ex. 1003, ¶ 65.)

Goldman discloses the combined use of acid inhibitors with NSAIDs,

including naproxen, to prevent the incidence of gastric ulcers and bleeding from

IPR2015-01344 Patent 8,858,996

12

the use of such NSAIDs. A POSA also would have recognized that acid inhibitors

are a well-known class of drugs that provide gastric acid inhibiting efficacy, and

therefore the POSA would have had a rationale (e.g., motivation) and a reasonable

expectation of success in substituting different acid inhibitor compounds into a

given combination therapy formulation where the acid inhibitor compound

contributes its individual therapeutic attributes (e.g., acid inhibition and gastric pH

raising) to the combination. (Ex. 1003, ¶ 66.)

Further, the POSA tasked with evaluating and selecting acid inhibitors

would have had a rationale (e.g., motivation) and a reasonable expectation of

success in employing more recently obtained and therapeutically more effective

compounds, such as PPIs, over previously known, less therapeutically effective

compounds, such as prostaglandins and H2 blockers. (Ex. 1003, ¶ 67.) Further, it

would have been obvious to a POSA to select Lindberg’s disclosed PPI

esomeprazole and substitute it for Goldman’s disclosed PPI omeprazole because

Lindberg specifically teaches:

It is desirable to obtain compounds with improved pharmacokinetic

and metabolic properties which will give an improved therapeutic

profile such as a lower degree of interindividual variation. The

present invention provides such compounds, which are novel salts of

single enantiomers of omeprazole . . . [a] more preferred embodiment

of the present invention is directed to an optically pure crystalline

IPR2015-01344 Patent 8,858,996

13

enantiomeric magnesium salt of omeprazole and method for the

preparation thereof.

(Ex. 1007, col. 1 ll. 50-63; Ex. 1003, ¶ 68.) Moreover, a POSA would have also

understood that “the optically pure salts are stable resisting racemization both in

neutral pH and basic pH” and that “[t]his high stability against racemization makes

it possible to use a single enantiomeric salt of the invention in therapy.” (Ex. 1007,

col. 3 ll. 48-55; Ex. 1003, ¶ 69.)

B. Claim 1:

Goldman in view of Remington in further view of Lindberg discloses each

limitation of claim 1.

1. A pharmaceutical composition in unit dosage form in the form of a tablet, said composition comprising:

Goldman discloses this limitation. (Ex. 1003, ¶ 71.) Specifically, Goldman

discloses, in unit dosage form, “one tablet of [a] pharmaceutical composition in

accordance with any of Examples 1-10.” (Ex. 1004, col. 8 ll. 4-7; Ex. 1003, ¶ 72.)

2. naproxen in an amount of 200-600 mg per unit dosage form; and

Goldman discloses this limitation. (Ex. 1003, ¶ 74.) Specifically, Goldman

discloses a composition containing “naproxen from 200 to 500 mg per dose.” (Ex.

1004, col. 5 ll. 9-19; Ex. 1003, ¶ 75.)

IPR2015-01344 Patent 8,858,996

14

3. esomeprazole in an amount of from 5 to 100 mg per unit dosage form,

Goldman in view of Remington in further view of Lindberg discloses this

limitation. (Ex. 1003, ¶ 76.) Specifically, Goldman discloses compositions

containing “proton pump inhibitor drugs including omeprazole.” (Ex. 1004, col. 5

ll. 9-31; Ex. 1003, ¶ 77.) Lindberg discloses “the [m]agnesium salt of (–)-5-

methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-

benzimidazole” in the “form of dosage units.” (Ex. 1007, col. 8 ll. 15-22, col. 5 ll.

25-26.) A POSA would have understood this compound to be the PPI

esomeprazole. (Ex. 1003, ¶ 79.) Lindberg further discloses that “oral . . . dosages

will be in the range of 5 to 500 mg per day of active substance.” (Ex. 1007, col. 6

ll. 21-25.) As discussed above, a POSA tasked with evaluating and selecting

compounds from the drug class (e.g., PPIs) would have had a rationale (e.g.,

motivation) and a reasonable expectation of success in replacing Goldman’s

disclosed PPI omeprazole with Lindberg’s disclosed PPI esomeprazole because

doing so would be a simple substitution of one known element for another to

obtain improved pharmacokinetic, metabolic, and therapeutic properties as taught

by Lindberg with predictable results. (Ex. 1007, col. 1 ll. 50-63; Ex. 1003, ¶ 81.)

4. wherein upon introduction of said unit dosage form into a medium, at least a portion of said esomeprazole is released regardless of the pH of the medium, and

Goldman in view of Remington in further view of Lindberg discloses this

IPR2015-01344 Patent 8,858,996

15

limitation. (Ex. 1003, ¶ 82.) Specifically, Goldman discloses that the tablets can

be prepared as described in Remington (Ex. 1005), which Goldman incorporates

by reference. (Ex. 1004, col. 6 ll. 26-33; Ex. 1003, ¶ 86.) Goldman provides that

“[v]arious conventional techniques for preparing medicament tablets or caplets can

be employed as would be known to those skilled in the art as is disclosed for

example by Remington’s Pharmaceutical Sciences.” (Ex. 1004, col. 6 ll. 26-33;

Ex. 1003, ¶ 87.) Remington discloses a unit dosage form “where unprotected drug

[esomeprazole] coated over the enteric coat is released in the stomach, while the

remainder [naproxen], being protected by the coating, is released further down the

gastrointestinal tract.” (Ex. 1005, at 1637; Ex. 1003, ¶ 90.) Lindberg discloses “the

[m]agnesium salt of (–)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-

methyl]sulfinyl]-1H-benzimidazole” in the “form of dosage units.” (Ex. 1007, col.

8 ll. 15-22, col. 5 ll. 25-26.) A POSA would have understood this compound to be

the PPI esomeprazole. Lindberg further discloses uncoated dosage units of

esomeprazole in the form of tablets. (Ex. 1007, col. 5 ll. 25-36; Ex. 1003, ¶ 85.)

In contrast to enteric coatings, a POSA would have understood that a given dosage

form may employ an uncoated drug, and that, following administration, such

formulations would release the drug upon contact with the surrounding medium

(e.g., immediate release upon entering the stomach) regardless of pH. (Ex. 1003, ¶

91.)

IPR2015-01344 Patent 8,858,996

16

5. release of at least a portion of said naproxen is inhibited unless the pH of said medium is 3.5 or higher.

Goldman in view of Remington discloses this limitation. (Ex. 1003, ¶ 93.)

As discussed above, Goldman discloses that the tablets comprising known

ingredients can be prepared as described in Remington (Ex. 1005), which Goldman

incorporates by reference. (Ex. 1004, col. 6 ll. 26-33; Ex. 1003, ¶ 95.) Goldman

discloses a composition containing “naproxen.” (Ex. 1004, col. 5 ll. 9-19; Ex.

1003, ¶ 94.) Remington further discloses using enteric coatings to delay the

release of drugs:

By definition, enteric coatings are those which remain intact in the

stomach . . . to delay the release of drugs which . . . may cause nausea

or bleeding by irritating the gastric mucosa (eg, aspirin . . .) . . . .

Thus, many modern enteric coatings are those [which] remain

undissociated in the low pH environment of the stomach, but readily

ionize when the pH rises to about 4 or 5.

(Ex. 1005, at 1637; Ex. 1003, ¶ 97.) Thus, Goldman in view of Remington teaches

that the release of naproxen is inhibited unless the pH of said medium is 3.5 or

higher. (Ex. 1005, at 1637; Ex. 1003, ¶ 99.)

C. Claim 2: The pharmaceutical composition of claim 1, wherein

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 1 obvious. Goldman in view of Remington further

discloses each limitation of claim 2.

IPR2015-01344 Patent 8,858,996

17

1. said naproxen is present in a core layer,

Goldman in view of Remington discloses this limitation. (Ex. 1003, ¶ 102.)

Goldman discloses a composition containing “naproxen.” (Ex. 1004, col. 5 ll. 9-

19; Ex. 1003, ¶ 104.) Remington further discloses using enteric coatings to form a

core layer. (Ex. 1005, at 1637; Ex. 1003, ¶ 106.)

2. wherein said core layer has a coating that inhibits its release from said unit dosage form unless said dosage form is in a medium with a pH of 3.5 or higher.

Goldman in view of Remington discloses this limitation. (Ex. 1003, ¶ 108.)

Remington discloses using enteric coatings to form a core layer to delay the release

of drugs from said core, as discussed above. (Ex. 1005, at 1637; Ex. 1003, ¶ 110.)

Thus, Goldman in view of Remington teaches that the release of naproxen is

inhibited unless the pH of said medium is 3.5 or higher. (Ex. 1005, at 1637; Ex.

1003, ¶ 111.)

D. Claim 3: The pharmaceutical composition of claim 1, wherein said unit dosage form is a multilayer tablet comprising a core layer and one or more layers outside of said core layer.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 1 obvious. Goldman in view of Remington further

discloses this limitation of claim 3. (Ex. 1003, ¶ 113.) Specifically, Remington

discloses a multilayered unit dosage form tablet, consisting of a core layer and an

outer layer where the core layer is coated/protected and the outer layer is

IPR2015-01344 Patent 8,858,996

18

unprotected/uncoated, and “where unprotected drug [esomeprazole] coated over

the enteric coat is released in the stomach, while the remainder [naproxen], being

protected by the coating, is released further down the gastrointestinal tract.” (Ex.

1005, at 1637; Ex. 1003, ¶ 115.)

E. Claim 4: The pharmaceutical composition of claim 3, wherein said core layer comprises naproxen.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 3 obvious. Goldman in view of Remington further

discloses this limitation of claim 4. (Ex. 1003, ¶ 119.) Remington discloses using

enteric coatings to form a core layer. (Ex. 1005, at 1637; Ex. 1003, ¶ 124.)

Goldman discloses a composition containing “naproxen.” (Ex. 1004, col. 5 ll. 9-

19; Ex. 1003, ¶ 121.)

F. Claim 5: The pharmaceutical composition of claim 3, wherein at least one of said one more layers outside said core layer comprises esomeprazole.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 3 obvious. Goldman in view of Remington in further view

of Lindberg further render obvious the one of said one more layers outside said

core layer of claim 5. (Ex. 1003, ¶ 127.) Lindberg discloses uncoated dosage units

of esomeprazole in the form of tablets. (Ex. 1007, col. 5 ll. 25-36; Ex. 1003, ¶

130.)

IPR2015-01344 Patent 8,858,996

19

G. Claim 6: The pharmaceutical composition of claim 3, wherein said one or more layers outside of said core layer do not contain naproxen.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 3 obvious. Goldman in view of Remington further

discloses this limitation of claim 6. (Ex. 1003, ¶ 137.) Remington discloses using

enteric coatings to form a core layer to delay the release of drugs from said core, as

discussed above. (Ex. 1005, at 1637; Ex. 1003, ¶ 143.) Further, Remington

discloses a multilayered unit dosage form “where unprotected drug [esomeprazole]

coated over the enteric coat is released in the stomach, while the remainder

[naproxen], being protected by the coating, is released further down the

gastrointestinal tract.” (Ex. 1005, at 1637; Ex. 1003, ¶ 142.) A POSA would have

understood that a typical purpose associated with enteric coatings is to delay

release of a drug until after the drug has exited the stomach to prevent nausea or

bleeding by irritating the gastric mucosa. For this reason, a POSA would have

been motivated to keep all of the naproxen in the core layer and not in one or more

layers outside of the core. (Ex. 1003, ¶ 146.)

H. Claim 7: The pharmaceutical composition of claim 1, further comprising at least one carrier.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 1 obvious. Lindberg further discloses this limitation of

claim 7. (Ex. 1003, ¶ 148.) Specifically, Lindberg discloses that “[t]he

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20

pharmaceutical formulations contain . . . a pharmaceutically acceptable carrier.”

(Ex. 1007, col. 5 ll. 12-19; Ex. 1003, ¶ 149.)

I. Claim 8: The pharmaceutical composition of claim 1, further comprising at least one auxiliary agent chosen from the group consisting of lubricants, preservatives, disintegrants, stabilizers, wetting agents, emulsifiers, salts, buffers, coloring agents, flavoring agents, and aromatic substances.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 1 obvious. Lindberg further discloses this limitation of

claim 8. (Ex. 1003, ¶ 151.) Specifically, Lindberg discloses the pharmaceutical

composition with auxiliary agents such as “lubricating agents such as magnesium

stearate, calcium stearate, sodium stearyl fumarate and polyethyleneglycol waxes.”

(Ex. 1007, col. 5 ll. 25-35; Ex. 1003, ¶ 152.)

J. Claim 9: The pharmaceutical composition of claim 1, further comprising at least one ingredient to adjust pH.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 1 obvious. Lindberg further discloses this limitation of

claim 9. (Ex. 1003, ¶ 155.) Specifically, Lindberg discloses the pharmaceutical

composition comprising at least one ingredient to adjust pH such as “stabilizing

substances such as alkaline compounds e.g. carbonates, hydroxides and oxides of

sodium, potassium, calcium, magnesium and the like . . . .” (Ex. 1007, col. 5 ll.

25-35; Ex. 1003, ¶ 156.) A POSA would have understood that Lindberg’s alkaline

compounds would have adjusted pH. (Ex. 1003, ¶ 157.)

IPR2015-01344 Patent 8,858,996

21

K. Claim 10: A method of treating a patient for pain or inflammation, comprising administering to said patient the pharmaceutical composition of claim 1.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 1 obvious and further discloses each limitation of claim 10.

(Ex. 1003, ¶ 159.) Specifically, Lindberg discloses that “[t]he compound of the

invention may also be used for treatment or prophylaxis of inflammatory

conditions.” (Ex. 1007, col. 2 ll. 30-32; Ex. 1003, ¶ 161.)

L. Claim 11: The method of claim 10, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 10 obvious. Lindberg further discloses this limitation of

claim 11. (Ex. 1003, ¶ 163.) Specifically, Lindberg discloses that “[t]he

compound of the invention may also be used for treatment or prophylaxis of

inflammatory conditions” such as “rheumatoid arthritis.” (Ex. 1007, col. 2 ll. 30-

34; Ex. 1003, ¶ 164.)

M. Claim 12:

Goldman in view of Remington in further view of Lindberg discloses each

limitation of claim 12.

1. A pharmaceutical composition in unit dosage form in the form of a tablet, said composition comprising:

Goldman discloses this limitation. (Ex. 1003, ¶ 166.) Specifically,

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22

Goldman discloses, in unit dosage form, “one tablet of [a] pharmaceutical

composition in accordance with any of Examples 1-10.” (Ex. 1004, col. 8 ll. 4-7;

Ex. 1003, ¶ 167.)

2. a core layer comprising naproxen, wherein

Goldman in view of Remington discloses this limitation. (Ex. 1003, ¶ 168.)

Specifically, Goldman discloses that the tablets can be prepared as described in

Remington (Ex. 1005), which Goldman incorporates by reference. (Ex. 1004, col.

6 ll. 26-33; Ex. 1003, ¶ 169.) Goldman provides that “[v]arious conventional

techniques for preparing medicament tablets or caplets can be employed as would

be known to those skilled in the art as is disclosed for example by Remington’s

Pharmaceutical Sciences.” (Ex. 1004, col. 6 ll. 26-33; Ex. 1003, ¶ 170.) Goldman

discloses a composition containing “naproxen.” (Ex. 1004, col. 5 ll. 9-19; Ex.

1003, ¶ 173.) Remington further discloses using enteric coatings to form a core

layer. (Ex. 1005, at 1637; Ex. 1003, ¶ 176.) Goldman provides a POSA with a

rationale, e.g., a specific teaching, suggestion and motivation, to look to

conventional techniques for preparing medicament tablets as set forth in

Remington and further incorporates by reference the disclosure of Remington.

(Ex. 1003, ¶ 172.)

IPR2015-01344 Patent 8,858,996

23

3. said core layer has a coating that inhibits release of said naproxen from said core layer unless said dosage form is in a medium with a pH of 3.5 or higher; and

Goldman in view of Remington discloses this limitation. (Ex. 1003, ¶ 178.)

Remington discloses using enteric coatings to form a core layer and to delay the

release of drugs from said core layer:

By definition, enteric coatings are those which remain intact in the

stomach . . . to delay the release of drugs which . . . may cause nausea

or bleeding by irritating the gastric mucosa (eg, aspirin . . .) . . . .

Thus, many modern enteric coatings are those [which] remain

undissociated in the low pH environment of the stomach, but readily

ionize when the pH rises to about 4 or 5.

(Ex. 1005, at 1637; Ex. 1003, ¶ 183.) Thus, Goldman in view of Remington

teaches that the release of naproxen is inhibited unless the pH of said medium is

3.5 or higher. (Ex. 1005, at 1637; Ex. 1003, ¶ 184.)

4. a layer comprising esomeprazole, wherein

Goldman in view of Remington in further view of Lindberg discloses this

limitation. (Ex. 1003, ¶ 184.) Specifically, Goldman discloses compositions

containing “proton pump inhibitor drugs including omeprazole.” (Ex. 1004, col. 5

ll. 9-31; Ex. 1003, ¶ 186.) Lindberg discloses “the [m]agnesium salt of (–)-5-

methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-

benzimidazole” in the “form of dosage units.” (Ex. 1007, col. 8 ll. 15-22, col. 5 ll.

IPR2015-01344 Patent 8,858,996

24

25-26.) A POSA would have understood this compound to be the PPI

esomeprazole. (Ex. 1003, ¶ 188.) Remington discloses a multilayered unit dosage

form tablet, consisting of a core layer and an outer layer where the core layer is

coated/protected and the outer layer is unprotected/uncoated, and “where

unprotected drug [esomeprazole] coated over the enteric coat is released in the

stomach, while the remainder [naproxen], being protected by the coating, is

released further down the gastrointestinal tract.” (Ex. 1005, at 1637; Ex. 1003, ¶

191.) As discussed above, a POSA tasked with evaluating and selecting

compounds from the drug class (e.g., PPIs) would have had a rationale (e.g.,

motivation) and a reasonable expectation of success in replacing Goldman’s

disclosed PPI omeprazole with Lindberg’s disclosed PPI esomeprazole into a layer

as taught by Remington because doing so would be a simple substitution of one

known element for another to obtain improved pharmacokinetic, metabolic, and

therapeutic properties as taught by Lindberg with predictable results. (Ex. 1007,

col. 1 ll. 50-63; Ex. 1003, ¶ 195.)

5. said layer has a non-enteric film coating that, upon ingestion by a patient, releases said esomeprazole into the stomach of said patient.

Goldman in view of Remington in further view of Lindberg discloses this

limitation. (Ex. 1003, ¶ 196.) Remington discloses “[f]ilm-[c]oated [t]ablets” as

“tablets which are covered with a thin layer or film of a water-soluble material”

IPR2015-01344 Patent 8,858,996

25

with the “same general characteristics as sugar coating . . . .” (Ex. 1005, at 1604;

Ex. 1003, ¶ 198.) Lindberg discloses “the [m]agnesium salt of (–)-5-methoxy-2-

[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole” in the

“form of dosage units.” (Ex. 1007, col. 8 ll. 15-22, col. 5 ll. 25-26.) A POSA

would have understood this compound to be the PPI esomeprazole. (Ex. 1003, ¶

202.) Lindberg further discloses uncoated dosage units of esomeprazole in the

form of tablets. (Ex. 1007, col. 5 ll. 25-36; Ex. 1003, ¶ 203.) In contrast to enteric

coatings, a POSA would have understood that a given dosage form may employ a

film coating, and that, following administration, such formulations would release

the drug upon contact with the surrounding medium (e.g., immediate release upon

entering the stomach). (Ex. 1003, ¶ 199.) A POSA would have had a rationale and

a reasonable expectation of success in preparing a combination therapy unit dosage

form having a film-coated drug (e.g., esomeprazole) that releases into the stomach

of said patient. (Ex. 1003, ¶ 200.)

N. Claim 13: The pharmaceutical composition of claim 12, wherein naproxen is present in said unit dosage form in an amount of 200-600 mg.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 12 obvious. Goldman further discloses this limitation of

claim 13. (Ex. 1003, ¶ 205.) Specifically, Goldman discloses a pharmaceutical

composition containing “naproxen from 200 to 500 mg per dose.” (Ex. 1004, col.

IPR2015-01344 Patent 8,858,996

26

5 ll. 9-19; Ex. 1003, ¶ 206.)

O. Claim 14: The pharmaceutical composition of claim 12, wherein esomeprazole is present in said unit dosage form in an amount of from 5 to 100 mg.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 12 obvious. Lindberg further discloses this limitation of

claim 14. (Ex. 1003, ¶ 208.) Specifically, Lindberg discloses esomeprazole with

“oral . . . dosages . . . in the range of 5 to 500 mg per day of active substance.”

(Ex. 1007, col. 6 ll. 21-25; Ex. 1003, ¶ 211.)

P. Claim 15: The pharmaceutical composition of claim 12, wherein

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 12 obvious. Goldman in view of Lindberg further

discloses each limitation of claim 15.

1. naproxen is present in said unit dosage form in an amount of between 200-600 mg and

Goldman discloses this limitation. (Ex. 1003, ¶ 214.) Specifically,

Goldman discloses a composition containing “naproxen from 200 to 500 mg per

dose.” (Ex. 1004, col. 5 ll. 9-19; Ex. 1003, ¶ 215.)

2. esomeprazole in an amount of from 5 to 100 mg per unit dosage form.

Lindberg discloses this limitation. (Ex. 1003, ¶ 216.) Specifically, Lindberg

discloses esomeprazole with “oral . . . dosages . . . in the range of 5 to 500 mg per

IPR2015-01344 Patent 8,858,996

27

day of active substance.” (Ex. 1007, col. 6 ll. 21-25; Ex. 1003, ¶ 219.)

Q. Claim 16: A method of treating a patient for pain or inflammation, comprising administering to said patient the pharmaceutical composition of claim 12.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 12 obvious and further discloses each limitation of claim

16. (Ex. 1003, ¶ 222.) Specifically, Lindberg discloses that “[t]he compound of

the invention may also be used for treatment or prophylaxis of inflammatory

conditions.” (Ex. 1007, col. 2 ll. 30-32; Ex. 1003, ¶ 223.)

R. Claim 17: The method of claim 16, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 16 obvious. Lindberg further discloses this limitation of

claim 17. (Ex. 1003, ¶ 225.) Specifically, Lindberg discloses that “[t]he

compound of the invention may also be used for treatment or prophylaxis of

inflammatory conditions” such as “rheumatoid arthritis.” (Ex. 1007, col. 2 ll. 30-

34; Ex. 1003, ¶ 226.)

S. Claim 18: A method of treating a patient for pain or inflammation, comprising administering to said patient the pharmaceutical composition of claim 15.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 15 obvious and further discloses each limitation of claim

IPR2015-01344 Patent 8,858,996

28

18. (Ex. 1003, ¶ 229.) Specifically, Lindberg discloses that “[t]he compound of

the invention may also be used for treatment or prophylaxis of inflammatory

conditions.” (Ex. 1007, col. 2 ll. 30-32; Ex. 1003, ¶ 230.)

T. Claim 19: The method of claim 18, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis.

As discussed above, Goldman in view of Remington in further view of

Lindberg renders claim 18 obvious. Lindberg further discloses this limitation of

claim 19. (Ex. 1003, ¶ 232.) Specifically, Lindberg discloses that “[t]he

compound of the invention may also be used for treatment or prophylaxis of

inflammatory conditions” such as “rheumatoid arthritis.” (Ex. 1007, col. 2 ll. 30-

34; Ex. 1003, ¶ 233.)

VIII. Ground 2: Gimet in view of Goldman and Lindberg Renders Obvious Claims 1-19

A. A POSA Would Have Combined Gimet, Goldman, and Lindberg

A POSA would have known that Gimet’s disclosed prostaglandin,

misoprostol, is an acid inhibitor. (Ex. 1003, ¶ 236.) As such, a POSA would have

understood that Gimet discloses a combination therapy oral unit dosage form

comprising an acid inhibitor (e.g., prostaglandin) in combination with an NSAID.

(Ex. 1003, ¶ 236.) Similarly, a POSA would have understood that Goldman

discloses a combination therapy oral unit dosage form comprising an acid inhibitor

(e.g., PPIs) in combination with an NSAID (e.g., naproxen). (Ex. 1003, ¶ 237.)

IPR2015-01344 Patent 8,858,996

29

The POSA would have known that NSAIDs are a well-known class of drugs

which provide analgesic effects, and therefore the POSA would have had a

rationale (e.g., motivation) and a reasonable expectation of success in substituting

different NSAID compounds in a given combination therapy formulation where

each drug contributes its individual therapeutic attributes to the combination. (Ex.

1003, ¶ 238.) Further, the POSA tasked with evaluating and selecting compounds

from the drug class (e.g., NSAIDs) would have had a rationale (e.g., motivation)

and a reasonable expectation of success in replacing Gimet’s disclosed NSAIDs

(e.g, piroxicam) with Goldman’s disclosed NSAIDs (e.g., naproxen) because doing

so would be a simple substitution of one known element for another to obtain

predictable results. (Ex. 1003, ¶ 239.) Accordingly, it would have been obvious to

a POSA to select naproxen from the listed NSAID/acid inhibitor combination

therapies of Goldman as a simple substitution for piroxicam used in the

NSAID/acid inhibitor combination therapies of Gimet.

A POSA also would have recognized that acid inhibitors are a well-known

class of drugs that provide gastric acid inhibiting efficacy, and therefore the POSA

would have had a rationale (e.g., motivation) and a reasonable expectation of

success in substituting different acid inhibitor compounds into a given combination

therapy formulation where the acid inhibitor compound contributes its individual

therapeutic attributes (e.g., acid inhibition and gastric pH raising) to the

IPR2015-01344 Patent 8,858,996

30

combination. (Ex. 1003, ¶ 241.)

Further, the POSA tasked with evaluating and selecting acid inhibitors

would have had a rationale (e.g., motivation) and a reasonable expectation of

success in employing more recently obtained and therapeutically more effective

compounds, such as PPIs, over previously known, less therapeutically effective

compounds, such as prostaglandins and H2 blockers. (Ex. 1003, ¶ 242.) Further, it

would have been obvious to a POSA to select Lindberg’s disclosed PPI

esomeprazole and substitute it for Gimet’s disclosed acid inhibitor (prostaglandin)

because Goldman specifically teaches that “[p]roton pump inhibitors have been

recently introduced as effective gastric acid inhibitors.” (Ex. 1004, col. 1 ll. 25-27;

Ex. 1003, ¶ 243.) It also would have been obvious to a POSA to select Lindberg’s

disclosed PPI esomeprazole and substitute it for Goldman’s disclosed PPI

omeprazole because Lindberg specifically teaches:

It is desirable to obtain compounds with improved pharmacokinetic

and metabolic properties which will give an improved therapeutic

profile such as a lower degree of interindividual variation. The

present invention provides such compounds, which are novel salts of

single enantiomers of omeprazole . . . [a] more preferred embodiment

of the present invention is directed to an optically pure crystalline

enantiomeric magnesium salt of omeprazole and method for the

preparation thereof.

(Ex. 1007, col. 1 ll. 50-63; Ex. 1003, ¶ 244.) Moreover, a POSA would have also

IPR2015-01344 Patent 8,858,996

31

understood that “the optically pure salts are stable resisting racemization both in

neutral pH and basic pH” and that “[t]his high stability against racemization makes

it possible to use a single enantiomeric salt of the invention in therapy.” (Ex. 1007,

col. 3 ll. 48-55; Ex. 1003, ¶ 245.)

B. Claim 1:

Gimet in view of Goldman and Lindberg discloses each limitation of claim

1.

1. A pharmaceutical composition in unit dosage form in the form of a tablet, said composition comprising:

Gimet discloses this limitation. (Ex. 1003, ¶ 248.) Specifically, Gimet

discloses, in unit dosage form, “a pharmaceutical composition which is a

core/mantle tablet.” (Ex. 1006, col. 3 ll. 8-14, Fig. 2; Ex. 1003, ¶ 249.)

2. naproxen in an amount of 200-600 mg per unit dosage form; and

Gimet in view of Goldman discloses this limitation. (Ex. 1003, ¶ 250.)

Specifically, Gimet discloses that “[t]he tablet 16 includes an inner core 18 of an

NSAID.” (Ex. 1006, col. 6 l. 25-28, Fig. 2; Ex. 1003, ¶ 251.) Gimet further

discloses, “[i]f the inner core is piroxicam, the . . . therapeutically acceptable

amount” is “10 to 20 mg.” (Ex. 1006, col. 4 l. 34-42.) Goldman also discloses a

composition containing “piroxicam from 10 to 20 mg per dose” or “naproxen from

200 to 500 mg per dose.” (Ex. 1004, col. 5 ll. 9-19, 21-24; Ex. 1003, ¶ 252.) As

IPR2015-01344 Patent 8,858,996

32

discussed above, a POSA tasked with evaluating and selecting compounds from

the drug class (e.g., NSAIDs) would have had a rationale (e.g., motivation) and a

reasonable expectation of success in replacing Gimet’s disclosed NSAIDs (e.g,

piroxicam) with Goldman’s disclosed NSAIDs (e.g., naproxen) because doing so

would be a simple substitution of one known element for another to obtain

predictable results. Accordingly, it would have been obvious to a POSA to select

naproxen from the listed NSAID/acid inhibitor combination therapies of Goldman

as a simple substitution for piroxicam used in the NSAID/acid inhibitor

combination therapies of Gimet.

3. esomeprazole in an amount of from 5 to 100 mg per unit dosage form,

Gimet in view of Lindberg discloses this limitation. (Ex. 1003, ¶ 255.)

Specifically, Gimet discloses that “[s]urrounding the core is a mantle coating

which consists of a prostaglandin.” (Ex. 1006, col. 3 ll. 8-14; Ex. 1003, ¶ 256.)

Lindberg discloses “the [m]agnesium salt of (–)-5-methoxy-2-[[4-methoxy-3,5-

dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole” in the “form of dosage

units.” (Ex. 1007, col. 8 ll. 15-22, col. 5 ll. 25-26.) A POSA would have

understood this compound to be the PPI esomeprazole. (Ex. 1003, ¶ 256.)

Lindberg further discloses that “oral . . . dosages will be in the range of 5 to 500

mg per day of active substance.” (Ex. 1007, col. 6 ll. 21-25.) As discussed above,

IPR2015-01344 Patent 8,858,996

33

it would have been obvious to a POSA to select Lindberg’s disclosed PPI

esomeprazole and substitute it for Gimet’s disclosed acid inhibitor (a

prostaglandin) in an effective equivalent dosage range because PPIs are more

effective as acid inhibitors. (Ex. 1003, ¶ 261.) As such, a POSA tasked with

evaluating and selecting compounds from the drug class (e.g., acid inhibitors)

would have had a rationale (e.g., motivation) and a reasonable expectation of

success in replacing Gimet’s disclosed acid inhibitor (prostaglandin) with

Lindberg’s disclosed PPI esomeprazole because doing so would be a simple

substitution of one known element for another to obtain improved

pharmacokinetic, metabolic, and therapeutic properties as taught by Lindberg with

predictable results. (Ex. 1007, col. 1 ll. 50-63; Ex. 1003, ¶ 262.)

4. wherein upon introduction of said unit dosage form into a medium, at least a portion of said esomeprazole is released regardless of the pH of the medium, and

Gimet in view of Lindberg discloses this limitation. (Ex. 1003, ¶ 263.)

Specifically, Gimet discloses that “[s]urrounding the core is a mantle coating

which consists of a prostaglandin.” (Ex. 1006, col. 3 ll. 8-14; Ex. 1003, ¶ 264.)

Lindberg discloses “the [m]agnesium salt of (–)-5-methoxy-2-[[4-methoxy-3,5-

dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole” in the “form of dosage

units.” (Ex. 1007, col. 8 ll. 15-22, col. 5 ll. 25-26.) A POSA would have

understood this compound to be the PPI esomeprazole. (Ex. 1003, ¶ 266.)

IPR2015-01344 Patent 8,858,996

34

Lindberg further discloses uncoated dosage units of esomeprazole in the form of

tablets. (Ex. 1007, col. 5 ll. 25-36; Ex. 1003, ¶ 267.) In contrast to enteric

coatings, a POSA would have understood that a given dosage form may employ an

uncoated drug, and that, following administration, such formulations would release

the drug upon contact with the surrounding medium (e.g., immediate release upon

entering the stomach) regardless of pH. (Ex. 1003, ¶ 268.)

5. release of at least a portion of said naproxen is inhibited unless the pH of said medium is 3.5 or higher.

Gimet in view of Goldman discloses this limitation. (Ex. 1003, ¶ 270.)

Specifically, Gimet discloses a tablet 16 that includes an NSAID inner core 18

surrounded by an enteric coating 20, the latter of which “aids in segregating the

NSAID from the prostaglandin and in directing the dissolution of the NSAID core

in the lower G.I. tract as opposed to the stomach.” (Ex. 1006, col. 6 ll. 24-36, Fig.

2; Ex. 1003, ¶ 271.) Goldman discloses a composition containing an NSAID

“naproxen.” (Ex. 1004, col. 5 ll. 9-19; Ex. 1003, ¶ 272.) A POSA would know

that a typical patient would have a pH in the small intestine after exiting the

stomach of greater than about 3.5. (Ex. 1003, ¶ 274.) Thus, the POSA would have

had a rationale and a reasonable expectation of success in preparing a unit dosage

form having a delayed release component, for example an enterically-coated drug

(e.g., an NSAID such as naproxen) to inhibit the release of the drug from the

IPR2015-01344 Patent 8,858,996

35

dosage form unless the pH of the surrounding medium (e.g., portions of the G.I.

tract after exiting the stomach) is 3.5 or higher. (Ex. 1003, ¶ 276.)

C. Claim 2: The pharmaceutical composition of claim 1, wherein

As discussed above, Gimet in view of Goldman and Lindberg renders claim

1 obvious. Gimet in view of Goldman further discloses each limitation of claim 2.

(Ex. 1003, ¶ 279.)

1. said naproxen is present in a core layer,

Gimet in view of Goldman discloses this limitation. (Ex. 1003, ¶ 280.)

Specifically, Gimet discloses that “[t]he tablet 16 includes an inner core 18 of an

NSAID.” (Ex. 1006, col. 6 l. 25-28, Fig. 2; Ex. 1003, ¶ 281.) Goldman discloses a

composition containing an NSAID “naproxen.” (Ex. 1004, col. 5 ll. 9-19; Ex.

1003, ¶ 282.)

2. wherein said core layer has a coating that inhibits its release from said unit dosage form unless said dosage form is in a medium with a pH of 3.5 or higher.

Gimet in view of Goldman discloses this limitation. (Ex. 1003, ¶ 283.)

Specifically, Gimet discloses a tablet 16 that includes an NSAID inner core 18

surrounded by an enteric coating 20, the latter of which “aids in segregating the

NSAID from the prostaglandin [coating] and in directing the dissolution of the

NSAID core in the lower G.I. tract as opposed to the stomach.” (Ex. 1006, col. 6 ll.

24-36, Fig. 2; Ex. 1003, ¶ 284.) Goldman discloses a composition containing an

NSAID

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IPR2015-01344 Patent 8,858,996

37

3 obvious. Gimet further discloses this limitation of claim 4. (Ex. 1003, ¶ 294.)

Specifically, Gimet discloses that “[t]he tablet 16 includes an inner core 18 of an

NSAID.” (Ex. 1006, col. 6 l. 25-28, Fig 2; Ex. 1003, ¶ 295.) Goldman discloses a

composition containing an NSAID “naproxen.” (Ex. 1004, col. 5 ll. 9-19; Ex.

1003, ¶ 296.)

F. Claim 5: The pharmaceutical composition of claim 3, wherein at least one of said one more layers outside said core layer comprises esomeprazole.

As discussed above, Gimet in view of Goldman and Lindberg renders claim

3 obvious. Gimet in view of Lindberg further discloses this limitation of claim 5.

(Ex. 1003, ¶ 298.) Specifically, Gimet discloses “a core/mantle tablet consisting of

a core of a nonsteroidal anti-inflammatory drug (NSAID)” and that “[s]urrounding

the core is a mantle coating which consists of a prostaglandin.” (Ex. 1006, col. 3

ll. 8-14, Fig. 1; Ex. 1003, ¶ 299.) Lindberg discloses uncoated dosage units of

esomeprazole in the form of tablets (Ex. 1007, col. 5 ll. 25-36).

G. Claim 6: The pharmaceutical composition of claim 3, wherein said one or more layers outside of said core layer do not contain naproxen.

As discussed above, Gimet in view of Goldman and Lindberg renders claim

3 obvious. Gimet further discloses this limitation of claim 6. (Ex. 1003, ¶ 305.)

Specifically, Gimet discloses “a core/mantle tablet consisting of a core of a

nonsteroidal anti-inflammatory drug (NSAID)” and that “[s]urrounding the core is

IPR2015-01344 Patent 8,858,996

38

a mantle coating which consists of a prostaglandin.” (Ex. 1006, col. 3 ll. 8-14; Ex.

1003, ¶ 306.) Gimet further discloses that the composition of the mantle consists

only of misoprostol, HPMC, crospovidone, colloidal silicon dioxide, hydrogenated

castor oil, and microcrystalline cellulose, and does not disclose any NSAID in the

mantle. (Ex. 1006, col. 7 ll. 25-44; Ex. 1003, ¶ 307.) Thus, based on the teachings

of Gimet, a POSA would have understood that the mantle does not contain any

NSAID such as naproxen. (Ex. 1003, ¶ 308.)

H. Claim 7: The pharmaceutical composition of claim 1, further comprising at least one carrier.

As discussed above, Gimet in view of Goldman and Lindberg renders claim

1 obvious. Gimet in view of Lindberg further discloses the at least one carrier of

claim 7. (Ex. 1003, ¶ 310.) Specifically, Gimet discloses that the pharmaceutical

composition includes “cornstarch.” (Ex. 1006, col. 7 ll. 25-44; Ex. 1003, ¶ 311.)

A POSA would have understood that cornstarch is a carrier. Lindberg further

discloses that “[t]he pharmaceutical formulations contain . . . a pharmaceutically

acceptable carrier.” (Ex. 1007, col. 5 ll. 12-19; Ex. 1003, ¶ 313.)

I. Claim 8: The pharmaceutical composition of claim 1, further comprising at least one auxiliary agent chosen from the group consisting of lubricants, preservatives, disintegrants, stabilizers, wetting agents, emulsifiers, salts, buffers, coloring agents, flavoring agents, and aromatic substances.

As discussed above, Gimet in view of Goldman and Lindberg renders claim

1 obvious. Gimet in view of Lindberg further discloses at least one auxiliary agent

IPR2015-01344 Patent 8,858,996

39

as per claim 8. (Ex. 1003, ¶ 315.) Specifically, Gimet discloses that various

auxiliary agents “such as binders, bulking agents, lubricants, fillers and the like”

can be combined with the pharmaceutical composition. (Ex. 1006, col. 4 ll. 28-33;

Ex. 1003, ¶ 316.) Lindberg further discloses the pharmaceutical composition with

auxiliary agents such as “lubricating agents such as magnesium stearate, calcium

stearate, sodium stearyl fumarate and polyethyleneglycol waxes.” (Ex. 1007, col.

5 ll. 25-35; Ex. 1003, ¶ 317.)

J. Claim 9: The pharmaceutical composition of claim 1, further comprising at least one ingredient to adjust pH.

As discussed above, Gimet in view of Goldman and Lindberg renders claim

1 obvious. Gimet in view of Lindberg further discloses this limitation of claim 9.

(Ex. 1003, ¶ 320.) Specifically, Gimet discloses that the composition includes

“sodium hydroxide.” (Ex. 1006, 8 ll. 18-45; Ex. 1003, ¶ 321.) Lindberg further

discloses that the pharmaceutical formulations may be mixed with at least one

ingredient to adjust pH, for example, “stabilizing substances such as alkaline

compounds e.g. carbonates, hydroxides and oxides of sodium, potassium, calcium,

magnesium and the like . . . .” (Ex. 1007, col. 5 ll. 25-35; Ex. 1003, ¶ 322.) A

POSA would have understood that Gimet’s sodium hydroxide and Lindberg’s

alkaline compounds would have adjusted pH. (Ex. 1003, ¶ 323.)

IPR2015-01344 Patent 8,858,996

40

K. Claim 10: A method of treating a patient for pain or inflammation, comprising administering to said patient the pharmaceutical composition of claim 1.

As discussed above, Gimet in view of Goldman and Lindberg renders claim

1 obvious and further discloses each limitation of claim 10. (Ex. 1003, ¶¶ 325-26.)

Specifically, Gimet discloses “[a] method of treating inflammation.” (Ex. 1006,

col. 12 ll. 41-44; Ex. 1003, ¶ 327.)

L. Claim 11: The method of claim 10, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis.

As discussed above, Gimet in view of Goldman and Lindberg renders claim

10 obvious. Gimet further discloses this limitation of claim 11. (Ex. 1003, ¶ 329.)

Specifically, Gimet discloses that the composition may be used to treat

“inflammatory conditions such as . . . osteoarthritis (OA) and rheumatoid arthritis

(RA).” (Ex. 1006, col. 1 ll. 18-23; Ex. 1003, ¶ 330.)

M. Claim 12:

Gimet in view of Goldman and Lindberg discloses each limitation of claim

12.

1. A pharmaceutical composition in unit dosage form in the form of a tablet, said composition comprising:

Gimet discloses this limitation. (Ex. 1003, ¶ 332.) Specifically, Gimet

discloses, in unit dosage form, “a pharmaceutical composition which is a

core/mantle tablet.” (Ex. 1006, col. 3 ll. 8-14, Fig. 2; Ex. 1003, ¶ 333.)

IPR2015-01344 Patent 8,858,996

41

2. a core layer comprising naproxen, wherein

Gimet in view of Goldman discloses this limitation. (Ex. 1003, ¶ 334.)

Specifically, Gimet discloses that “[t]he tablet 16 includes an inner core 18 of an

NSAID.” (Ex. 1006, col. 6 l. 25-28, Fig. 2; Ex. 1003, ¶ 335.) Gimet further

discloses, “[i]f the inner core is piroxicam, the . . . therapeutically acceptable

amount” is “10 to 20 mg.” (Ex. 1006, col. 4 l. 34-42.) Goldman also discloses a

composition containing “piroxicam from 10 to 20 mg per dose” or “naproxen from

200 to 500 mg per dose.” (Ex. 1004, col. 5 ll. 9-19, 21-24; Ex. 1003, ¶ 336.) As

discussed above, a POSA tasked with evaluating and selecting compounds from

the drug class (e.g., NSAIDs) would have had a rationale (e.g., motivation) and a

reasonable expectation of success in replacing Gimet’s disclosed NSAIDs (e.g,

piroxicam) with Goldman’s disclosed NSAIDs (e.g., naproxen) because doing so

would be a simple substitution of one known element for another to obtain

predictable results. Accordingly, it would have been obvious to a POSA to select

naproxen from the listed NSAID/acid inhibitor combination therapies of Goldman

as a simple substitution for piroxicam used in the NSAID/acid inhibitor

combination therapies of Gimet.

3. said core layer has a coating that inhibits release of said naproxen from said core layer unless said dosage form is in a medium with a pH of 3.5 or higher; and

Gimet in view of Goldman discloses this limitation. (Ex. 1003, ¶ 339.)

IPR2015-01344 Patent 8,858,996

42

Specifically, Gimet discloses a tablet 16 that includes an NSAID inner core 18

surrounded by an enteric coating 20, the latter of which “aids in segregating the

NSAID from the prostaglandin [coating] and in directing the dissolution of the

NSAID core in the lower G.I. tract as opposed to the stomach.” (Ex. 1006, col. 6 ll.

24-36, Fig. 2; Ex. 1003, ¶ 340.) Goldman discloses a composition containing an

NSAID “naproxen.” (Ex. 1004, col. 5 ll. 9-19; Ex. 1003, ¶ 341.) A POSA would

know that a typical patient would have a pH in the small intestine after exiting the

stomach of greater than about 3.5. (Ex. 1003, ¶ 343.) Thus, the POSA would have

had a rationale and a reasonable expectation of success in preparing a unit dosage

form having a delayed release component, for example an enterically-coated drug

(e.g., an NSAID such as naproxen) to inhibit the release of the drug from the

dosage form unless the pH of the surrounding medium (e.g., portions of the G.I.

tract after exiting the stomach) is 3.5 or higher. (Ex. 1003, ¶ 345.)

4. a layer comprising esomeprazole, wherein

Gimet in view of Lindberg discloses this limitation. (Ex. 1003, ¶ 346.)

Specifically, Gimet discloses that “[s]urrounding the core is a mantle coating

which consists of a prostaglandin.” (Ex. 1006, col. 3 ll. 8-14; Ex. 1003, ¶ 347.)

Lindberg discloses “the [m]agnesium salt of (–)-5-methoxy-2-[[4-methoxy-3,5-

dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole” in the “form of dosage

units.” (Ex. 1007, col. 8 ll. 15-22, col. 5 ll. 25-26.) A POSA would have

IPR2015-01344 Patent 8,858,996

43

understood this compound to be the PPI esomeprazole. (Ex. 1003, ¶ 350.) As

discussed above, it would have been obvious to a POSA to select Lindberg’s

disclosed PPI esomeprazole and substitute it for Gimet’s disclosed acid inhibitor (a

prostaglandin) in an effective equivalent dosage range because PPIs are more

effective as acid inhibitors. (Ex. 1003, ¶ 351.) As such, a POSA tasked with

evaluating and selecting compounds from the drug class (e.g., acid inhibitors)

would have had a rationale (e.g., motivation) and a reasonable expectation of

success in replacing Gimet’s disclosed acid inhibitor (prostaglandin) with

Lindberg’s disclosed PPI esomeprazole because doing so would be a simple

substitution of one known element for another to obtain improved

pharmacokinetic, metabolic, and therapeutic properties as taught by Lindberg with

predictable results. (Ex. 1007, col. 1 ll. 50-63; Ex. 1003, ¶ 352.)

5. said layer has a non-enteric film coating that, upon ingestion by a patient, releases said esomeprazole into the stomach of said patient.

Gimet in view of Lindberg discloses this limitation. (Ex. 1003, ¶ 353.)

Specifically, Gimet discloses that “[s]urrounding the core is a mantle coating

which consists of a prostaglandin.” (Ex. 1006, col. 3 ll. 8-14; Ex. 1003, ¶ 354.)

Gimet further discloses that the composition of the mantle includes

“hydroxypropyl methylcellulose (HPMC).” (Ex. 1006, col. 7 ll. 25-44; Ex. 1003, ¶

355.) A POSA would have understood HPMC to be a film coating. (Id.)

IPR2015-01344 Patent 8,858,996

44

Lindberg discloses “the [m]agnesium salt of (–)-5-methoxy-2-[[4-methoxy-3,5-

dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole” in the “form of dosage

units.” (Ex. 1007, col. 8 ll. 15-22, col. 5 ll. 25-26.) A POSA would have

understood this compound to be the PPI esomeprazole. (Ex. 1003, ¶ 357.)

Lindberg further discloses esomeprazole pellets “coated with a solution of

hydroxypropyl methylcellulose.” (Ex. 1007, col. 13 ll. 3-5; Ex. 1003, ¶ 358.) In

contrast to enteric coatings, a POSA would have understood that a given dosage

form may employ a film coating, and that, following administration, such

formulations would release the drug upon contact with the surrounding medium

(e.g., immediate release upon entering the stomach). (Ex. 1003, ¶ 359.) A POSA

would have had a rationale and a reasonable expectation of success in preparing a

combination therapy unit dosage form having a film-coated drug (e.g.,

esomeprazole) that releases into the stomach of said patient. (Ex. 1003, ¶ 360.)

N. Claim 13: The pharmaceutical composition of claim 12, wherein naproxen is present in said unit dosage form in an amount of 200-600 mg.

As discussed above, Gimet in view of Goldman and Lindberg renders claim

12 obvious. Gimet in view of Goldman further discloses this limitation of claim

13. (Ex. 1003, ¶ 362.) Specifically, Gimet discloses that “[t]he tablet 16 includes

an inner core 18 of an NSAID.” (Ex. 1006, col. 6 l. 25-28, Fig 2; Ex. 1003, ¶ 363.)

Gimet further discloses, “[i]f the inner core is piroxicam, the . . . therapeutically

IPR2015-01344 Patent 8,858,996

45

acceptable amount” is “10 to 20 mg.” (Ex. 1006, col. 4 l. 34-42.) Goldman also

discloses a composition containing “piroxicam from 10 to 20 mg per dose” or

“naproxen from 200 to 500 mg per dose.” (Ex. 1004, col. 5 ll. 9-19, 21-24; Ex.

1003, ¶ 364.)

O. Claim 14: The pharmaceutical composition of claim 12, wherein esomeprazole is present in said unit dosage form in an amount of from 5 to 100 mg.

As discussed above, Gimet in view of Goldman and Lindberg renders claim

12 obvious. Gimet in view of Lindberg further discloses this limitation of claim

14. (Ex. 1003, ¶ 366.) Specifically, Lindberg discloses esomeprazole with “oral . .

. dosages . . . in the range of 5 to 500 mg per day of active substance.” (Ex. 1007,

col. 6 ll. 21-25; Ex. 1003, ¶ 371.)

P. Claim 15: The pharmaceutical composition of claim 12, wherein

As discussed above, Gimet in view of Goldman and Lindberg renders claim

12 obvious. Gimet in view of Goldman and Lindberg further discloses each

limitation of claim 15.

1. naproxen is present in said unit dosage form in an amount of between 200-600 mg and

Gimet in view of Goldman discloses this limitation. (Ex. 1003, ¶ 375.)

Specifically, Gimet discloses that “[t]he tablet 16 includes an inner core 18 of an

NSAID.” (Ex. 1006, col. 6 l. 25-28, Fig 2; Ex. 1003, ¶ 376.) Goldman discloses a

composition containing an NSAID “naproxen from 200 to 500 mg per dose.” (Ex.

IPR2015-01344 Patent 8,858,996

46

1004, col. 5 ll. 9-19; Ex. 1003, ¶ 377.)

2. esomeprazole in an amount of from 5 to 100 mg per unit dosage form.

Gimet in view of Lindberg further discloses this limitation. (Ex. 1003, ¶

378.) Specifically, Lindberg discloses esomeprazole with “oral . . . dosages . . . in

the range of 5 to 500 mg per day of active substance.” (Ex. 1007, col. 6 ll. 21-25;

Ex. 1003, ¶ 383.)

Q. Claim 16: A method of treating a patient for pain or inflammation, comprising administering to said patient the pharmaceutical composition of claim 12.

As discussed above, Gimet in view of Goldman and Lindberg renders claim

12 obvious and further discloses each limitation of claim 16. (Ex. 1003, ¶ 387.)

Specifically, Gimet discloses “[a] method of treating inflammation.” (Ex. 1006,

col. 12 ll. 41-44; Ex. 1003, ¶ 388.)

R. Claim 17: The method of claim 16, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis.

As discussed above, Gimet in view of Goldman and Lindberg renders claim

16 obvious. Gimet further discloses this limitation of claim 17. (Ex. 1003, ¶ 390.)

Specifically, Gimet discloses that the composition may be used to treat

“inflammatory conditions such as . . . osteoarthritis (OA) and rheumatoid arthritis

(RA).” (Ex. 1006, col. 1 ll. 18-23; Ex. 1003, ¶ 391.)

IPR2015-01344 Patent 8,858,996

47

S. Claim 18: A method of treating a patient for pain or inflammation, comprising administering to said patient the pharmaceutical composition of claim 15.

As discussed above, Gimet in view of Goldman and Lindberg renders claim

15 obvious and further discloses each limitation of claim 18. (Ex. 1003, ¶ 394.)

Specifically, Gimet discloses “[a] method of treating inflammation.” (Ex. 1006,

col. 12 ll. 41-44; Ex. 1003, ¶ 395.)

T. Claim 19: The method of claim 18, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis.

As discussed above, Gimet in view of Goldman and Lindberg renders claim

18 obvious. Gimet further discloses this limitation of claim 19. (Ex. 1003, ¶ 397.)

Specifically, Gimet discloses that the composition may be used to treat

“inflammatory conditions such as . . . osteoarthritis (OA) and rheumatoid arthritis

(RA).” (Ex. 1006, col. 1 ll. 18-23; Ex. 1003, ¶ 398.)

IX. Ground 3: The Plachetka ’255 Publication Anticipates Claims 1-19

A. The Earliest Effective Filing Date of the ’996 Patent is May 16, 2005 Due to a Break in Priority

The ’996 Patent issued on October 14, 2014 from U.S. Patent App. No.

14/244,471 (“the ’471 Application”) (Ex. 1002). The ’471 Application, filed on

April 3, 2014, is a sixth-generation descendent of U.S. Patent Prov. App. No.

60/294,588 (“the ’588 Application”) (Ex. 1009), filed on June 1, 2001. The ’996

Patent claims priority to the ’588 Application and to the first-generation

IPR2015-01344 Patent 8,858,996

48

descendent of the ’588 Application, U.S. Patent App. No. 10/158,216 (“the ’216

Application”) (Ex. 1010), filed on May 31, 2002 (collectively, “the pre-2003

applications”). Despite the claim of priority, the ’996 Patent claims are not

supported by the pre-2003 applications because the claims are broader than the

disclosures of the pre-2003 applications.

The ’216 Application published as the Plachetka ’255 Publication (Ex. 1008)

on April 10, 2003, more than two years before the filing of any application to

which the ’996 Patent may claim priority. The next application in the chain, U.S.

Patent App. No. 11/129,320 (“the ’320 Application”) (Ex. 1011), filed on May 16,

2005, is the earliest application that supports the ’996 Patent claims. As such, the

effective filing date of the claims of the ’996 Patent is no earlier than May 16,

2005, and the Plachetka ’255 Publication is prior art to the ’996 Patent under

35 U.S.C. § 102(b).

The following flow chart shows the application chain that preceded the ’996

Patent and the priority break:

IPR2015-01344 Patent 8,858,996

49

Application Chain Leading to U.S. Patent No. 8,858,996

US Prov. App. 60/294,588 Filed June 1, 2001

App. No. 10/158,216 Filed May 31, 2002

PRIORITY BREAK

CIP App. No. 11/129,320 Filed May 16, 2005

DIV App. No. 12/553,804 Filed September 3, 2009

DIV App. No. 13/215,855 Filed August 23, 2011

CON App. No. 14/045,156 October 3, 2013

CON App. No.14/244,471 April 3, 2014

US Patent No. 6,926,907

More than one year

US2003/0069255 Published April 10, 2003

abandoned

US Patent No. 8,557,285

US Patent No. 8,206,741

pre-2003 applications

The ’216 Application does not support the ’996 Patent claims

US Patent No. 8,858,996

US Patent No. 8,852,636

IPR2015-01344 Patent 8,858,996

50

Under the broadest reasonable construction standard, the ’996 Patent claims

are broad enough to encompass naproxen/esomeprazole pharmaceutical

compositions that:

release at least a portion of the naproxen immediately at any pH;

“inhibit” or slow down the release of all of the naproxen at a pH

below 3.5 until the pH reaches 3.5 or higher; and

do not have a “coordinated release” or sequential release of the

esomeprazole and the naproxen.

The break in the priority arises because neither of the two pre-2003

applications has a written description to support a naproxen/esomeprazole

pharmaceutical composition with any of these features. Indeed, these features are

contrary to much of what the pre-2003 applications do support. The pre-2003

applications disclose NSAID/acid inhibitor pharmaceutical compositions that:

release none of the NSAID immediately;

“prevent” or stop the release of all of the NSAID until reaching a pH

of 3.5 or higher; and

have a “coordinated release” or sequential release of the acid inhibitor

and the NSAID.

The pre-2003 applications describe pharmaceutical compositions that

“prevent” or stop the release of all of the NSAID by surrounding the NSAID with

IPR2015-01344 Patent 8,858,996

51

an enteric coating. The ’996 Patent claims are broader because they require only a

portion of the NSAID (naproxen) to be subject to an “inhibited” release. As such,

the ’996 Patent claims are broad enough to cover pharmaceutical compositions

wherein at least some of the naproxen is released immediately at any pH.

Moreover, the ’996 Patent claims all recite a coating that “inhibits” or slows

down the release of at least a portion the naproxen at a pH below 3.5 unless the pH

reaches 3.5 or higher, rather than “preventing” or stopping the release until the pH

is 3.5 or higher. As discussed above in Section VI(A), the meaning of “inhibit” is

broader than the meaning of “prevent.” “Inhibit” means “to slow down, hinder, or

prevent.” “Prevent” means “to stop.” Because “inhibit” means either to slow

down or to stop, the ’996 Patent claims read on a coating that merely decreases the

release rate of the naproxen, instead of stopping the release of naproxen, until the

pH of the medium is 3.5 or higher.

Finally, contrary to the disclosure in the pre-2003 applications, none of the

claims of the ’996 Patent recite a “coordinated release” or sequential release of the

esomeprazole and the naproxen as an element. The ’996 Patent claims are broad

enough to cover pharmaceutical compositions that release at least a portion of

esomeprazole and naproxen simultaneously.

Because all of the claims of the ’996 Patent exceed the scope of the

disclosure in the pre-2003 applications, they cannot rely on the pre-2003

applicat

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IPR2015-01344 Patent 8,858,996

53

between 200 mg and 600 mg. See ¶ [0012]; see also Claim 11.

esomeprazole in an amount of from 5 to 100 mg per unit dosage form,

For example, the proton pump inhibitor omeprazole should be present in tablets or capsules in an amount from 5 to 50 mg, with about 20 mg per unit dosage form being preferred. Other typical amounts are: esomeprazole, 5-100 mg, with about 40 mg per unit dosage form being preferred . . . . See ¶ [0041]; see also Claim 5.

wherein upon introduction of said unit dosage form into a medium, at least a portion of said esomeprazole is released regardless of the pH of the medium, and

The outermost layer contains an “acid inhibitor” in an effective amount which is released from the dosage form immediately after administration to the patient. See ¶ [0051]; see also ¶¶ [0011], [0048]; Fig. 1 and Claim 5. The term “acid inhibitor” refers to agents that inhibit gastric acid secretion and increase gastric pH. . . . . other agents that may be effectively used include proton pump inhibitors such as omeprazole, esomeprazole, pantoprazole, lansoprazole or rabeprazole. See ¶ [0011].

release of at least a portion of said naproxen is inhibited unless the pH of said medium is 3.5 or higher.

The function of the third layer is to prevent the release of naproxen sodium until the dosage form reaches an environment where the pH is above about 4 or 5. The enteric coating does not dissolve in areas of the GI tract where the pH may be below about 4 or 5 such as in an unprotected stomach . . . The coating dissolves only when the local pH is above, for example, 5.5 and, as a result, naproxen sodium is released. See ¶ [0050]; see also ¶¶ [0012]-[0015] and Claims 1, 12, and 18.

2. The pharmaceutical composition of claim 1, wherein

As shown above, the Plachetka ’255 Publication anticipates claim 1. See supra.

said naproxen is present in a core layer,

FIG. 1 is a schematic diagram of a four layer tablet dosage form. There is a naproxen core layer surrounded by a barrier layer. See ¶ [0017]; see also ¶¶ [0012]-[0015] and Claims 9 and 12-14.

wherein said core layer has a coating that inhibits its release from said unit dosage form

The function of the third layer is to prevent the release of naproxen sodium until the dosage form reaches an environment where the pH is above about 4 or 5. The enteric coating does not dissolve in areas of the GI tract where the pH may be below about 4 or 5 such as in an

IPR2015-01344 Patent 8,858,996

54

unless said dosage form is in a medium with a pH of 3.5 or higher.

unprotected stomach . . . The coating dissolves only when the local pH is above, for example, 5.5 and, as a result, naproxen sodium is released. See ¶ [0050]; see also ¶¶ [0012]-[0015] and Claims 1, 12, and 18.

3.The pharmaceutical composition of claim 1, wherein

As shown above, the Plachetka ’255 Publication anticipates claim 1. See supra.

said unit dosage form is a multilayer tablet comprising a core layer and one or more layers outside of said core layer.

FIG. 1 is a schematic diagram of a four layer tablet dosage form. There is a naproxen core layer surrounded by a barrier layer . . . Finally, there is an outer layer that releases an acid inhibitor . . . . See ¶ [0017]; see also ¶¶ [0012]-[0015] and Claims 1, 12, 13, and 14.

4.The pharmaceutical composition of claim 3, wherein

As shown above, the Plachetka ’255 Publication anticipates claim 3. See supra.

said core layer comprises naproxen.

FIG. 1 is a schematic diagram of a four layer tablet dosage form. There is a naproxen core layer surrounded by a barrier layer. See ¶ [0017]; see also ¶¶ [0012]-[0015] and Claims 1, 9, 12, 13, and 14.

5.The pharmaceutical composition of claim 3, wherein

As shown above, the Plachetka ’255 Publication anticipates claim 3. See supra.

at least one of said one more layers outside said core layer comprises esomeprazole.

The outermost layer contains an “acid inhibitor” in an effective amount which is released from the dosage form immediately after administration to the patient. See ¶ [0051]; see also ¶¶ [0011], [0048]; Fig. 1 and Claim 5. The term “acid inhibitor” refers to agents that inhibit gastric acid secretion and increase gastric pH. . . . . other agents that may be effectively used include proton pump inhibitors such as omeprazole, esomeprazole, pantoprazole, lansoprazole or rabeprazole. See ¶ [0011].

6.The pharmaceutical composition of claim

As shown above, the Plachetka ’255 Publication anticipates claim 3. See supra.

IPR2015-01344 Patent 8,858,996

55

3, wherein said one or more layers outside of said core layer do not contain naproxen.

A schematic diagram of a four layer tablet dosage form is shown in FIG. 1. The first layer contains naproxen . . . . The second layer is a barrier layer which protects the first layer containing naproxen . . . the core naproxen sodium tablet is coated with coating ingredients such as Opaspray®K-1-4210A or Opadry®YS-1-7006 (Colorcon, West Point, Pa.). Polymer film coating ingredients such as hydroxypropylmethylcellulose 2910 and polyethylene glycol 8000 in a coating suspension may also be used. The function of the third layer is to prevent the release of naproxen sodium until the dosage form reaches an environment where the pH is above about 4 or 5. . . .Methacrylic acid copolymers are used as the enteric coating ingredient, triethyl citrate and dibutyl phthalate are plasticisers, and ammonium hydroxide is used to adjust the pH of the dispersion . . .The outermost layer contains an “acid inhibitor”. . . The acid inhibitor in the present example is a proton pump inhibitor or, preferably the H2 blocker famotidine. . . A typical film coating formulation contains Opadry Clear®YS-1-7006 . . . Other ingredients may include: plasticisers such as triethyl citrate, dibutyl phthalate, and polyethylene glycol; anti-adhering agents such as talc; lubricating ingredients such as magnesium stearate; and opacifiers such as titanium dioxide. In addition, the pH of the film coating solution can be adjusted to aid in dissolution of the [acid inhibitor]. See ¶¶ [0048]-[0051]; see also ¶¶ [0064]-[0067]; and [0073]-[0076].

7.The pharmaceutical composition of claim 1, further comprising

As shown above, the Plachetka ’255 Publication anticipates claim 1. See supra.

at least one carrier. The pharmaceutical compositions of the invention include tablets, dragees, liquids and capsules and can be made in accordance with methods that are standard in the art . . . Drugs and drug combinations will typically be prepared in admixture with conventional excipients. Suitable carriers include, but are not limited to: water; salt solutions; alcohols; gum arabic; vegetable oils; benzyl

IPR2015-01344 Patent 8,858,996

56

alcohols; polyethylene glycols; gelatin; carbohydrates such as lactose, amylose or starch; magnesium stearate; talc; silicic acid; paraffin; perfume oil; fatty acid esters; hydroxymethylcellulose; polyvinylpyrrolidone; etc. See ¶ [0043].

8.The pharmaceutical composition of claim 1, further comprising

As shown above, the Plachetka ’255 Publication anticipates claim 1. See supra.

at least one auxiliary agent chosen from the group consisting of lubricants, preservatives, disintegrants, stabilizers, wetting agents, emulsifiers, salts, buffers, coloring agents, flavoring agents, and aromatic substances.

The pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents such as: lubricants, preservatives, disintegrants; stabilizers; wetting agents; emulsifiers; salts; buffers; coloring agents; flavoring agents; or aromatic substances. See ¶ [0043].

9.The pharmaceutical composition of claim 1, further comprising

As shown above, the Plachetka ’255 Publication anticipates claim 1. See supra.

at least one ingredient to adjust pH.

A pharmaceutically acceptable enteric coating surrounds the naproxen core . . . It contains methacrylic acid copolymers which prevent the release of naproxen in the unprotected stomach. Also included [is] . . . sodium hydroxide which is used to adjust the pH of the dispersion. See ¶ [0053]; see also ¶ [0067]. Omeprazole granules contain an alkalizing excipient such as sodium bicarbonate. See ¶ [0083].

10. A method of treating a patient for pain or inflammation, comprising

The invention includes methods of treating a patient for pain, inflammation and/or other conditions by administering the pharmaceutical compositions described above. See ¶ [0014]; see also Claim 22.

adminispatient tpharmacompos1. 11. Theclaim 10said paiinflammto eitherosteoartrheumat12. A phcomposdosage form ofcomposcompris

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IPR2015-01344 Patent 8,858,996

58

a layer comprising esomeprazole, wherein

The outermost layer contains an “acid inhibitor” in an effective amount which is released from the dosage form immediately after administration to the patient. See ¶ [0051]; see also ¶¶ [0011], [0048]; Fig. 1 and Claim 5. The term “acid inhibitor” refers to agents that inhibit gastric acid secretion and increase gastric pH. . . . . other agents that may be effectively used include proton pump inhibitors such as omeprazole, esomeprazole, pantoprazole, lansoprazole or rabeprazole. See ¶ [0011].

said layer has a non-enteric film coating that, upon ingestion by a patient, releases said esomeprazole into the stomach of said patient.

A typical film coating formulation contains Opadry Clear®YS-1-7006 which helps in the formation of the film and in uniformly distributing [the acid inhibitor] within the fourth layer . . . The film coating is thin and rapidly releases [acid inhibitor] for absorption. See ¶ [0051].

13. The pharmaceutical composition of claim 12, wherein

As shown above, the Plachetka ’255 Publication anticipates claim 12. See supra.

naproxen is present in said unit dosage form in an amount of 200-600 mg.

The pharmaceutical composition also contains a non-steroidal anti-inflammatory drug in an amount effective to reduce or eliminate pain or inflammation. . . . The most preferred NSAID is naproxen in an amount of between 50 mg and 1500 mg, and more preferably, in an amount of between 200 mg and 600 mg. See ¶ [0012]; see also Claim 11.

14. The pharmaceutical composition of claim 12, wherein

As shown above, the Plachetka ’255 Publication anticipates claim 12. See supra.

esomeprazole is present in said unit dosage form in an amount of from 5 to 100 mg.

For example, the proton pump inhibitor omeprazole should be present in tablets or capsules in an amount from 5 to 50 mg, with about 20 mg per unit dosage form being preferred. Other typical amounts are: esomeprazole, 5-100 mg, with about 40 mg per unit dosage form being preferred . . . . See ¶ [0041]; see also Claim 5.

15. The As shown above, the Plachetka ’255 Publication anticipates

IPR2015-01344 Patent 8,858,996

59

pharmaceutical composition of claim 12, wherein

claim 12. See supra.

naproxen is present in said unit dosage form in an amount of between 200-600 mg and

The pharmaceutical composition also contains a non-steroidal anti-inflammatory drug in an amount effective to reduce or eliminate pain or inflammation. . . . The most preferred NSAID is naproxen in an amount of between 50 mg and 1500 mg, and more preferably, in an amount of between 200 mg and 600 mg. See ¶ [0012]; see also Claim 11.

esomeprazole in an amount of from 5 to 100 mg per unit dosage form.

For example, the proton pump inhibitor omeprazole should be present in tablets or capsules in an amount from 5 to 50 mg, with about 20 mg per unit dosage form being preferred. Other typical amounts are: esomeprazole, 5-100 mg, with about 40 mg per unit dosage form being preferred . . . . See ¶ [0041]; see also Claim 5.

16. A method of treating a patient for pain or inflammation, comprising

The invention includes methods of treating a patient for pain, inflammation and/or other conditions by administering the pharmaceutical compositions described above. See ¶ [0014]; see also Claim 22.

administering to said patient the pharmaceutical composition of claim 12.

See claim 12, supra.

17. The method of claim 16, wherein

As shown above, the Plachetka ’255 Publication anticipates claim 16. See supra.

said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis.

Although the method may be used for any condition in which an NSAID is effective, it is expected that it will be particularly useful in patients with osteoarthritis or rheumatoid arthritis. See ¶ [0014]; see also Claim 23.

18. A method of treating a patient for pain or inflammation, comprising

The invention includes methods of treating a patient for pain, inflammation and/or other conditions by administering the pharmaceutical compositions described above. See ¶ [0014]; see also Claim 22.

administering to said See claim 15, supra.

IPR2015-01344 Patent 8,858,996

60

patient the pharmaceutical composition of claim 15. 19. The method of claim 18, wherein

As shown above, the Plachetka ’255 Publication anticipates claim 18. See supra.

said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis.

Although the method may be used for any condition in which an NSAID is effective, it is expected that it will be particularly useful in patients with osteoarthritis or rheumatoid arthritis. See ¶ [0014]; see also Claim 23.

X. Any Secondary Considerations of Nonobviousness Would Fail

CFAD is unaware of any evidence of secondary considerations of

nonobviousness in this case. (Ex. 1003, ¶ 26.)

XI. Conclusion

CFAD respectfully requests that the Board institute an Inter Partes Review

of claims 1-19 on the grounds set forth above.

IPR2015-01344 Patent 8,858,996

61

Date: June 5, 2015 Respectfully submitted,

/Amy E. LaValle/ Amy E. LaValle (Reg. No. 51,092) Jerry C. Harris, Jr. (Reg. No. 66,822) Rodney B. Carroll (Reg. No. 39,624) Conley Rose, P.C. 5601 Granite Parkway, Suite 500 Plano, Texas 75024 (972) 731-2288 (phone) (972) 731-2289 (fax) [email protected] [email protected] [email protected] Counsel for Petitioner Coalition for Affordable Drugs VII LLC

IPR2015-01344 Patent 8,858,996

62

CERTIFICATE OF SERVICE

Pursuant to 37 C.F.R. § 42.6(e), I hereby certify that on June 5, 2015 a copy

of the foregoing PETITION FOR INTER PARTES REVIEW was provided via

FedEx, overnight delivery, to the Patent Owner by serving the correspondence

address of record for the ’996 Patent:

Steven L. Highlander Parker Highlander PLLC 1120 South Capital of Texas Highway Bldg. 1, Suite 200 Austin, Texas 78746

Date: June 5, 2015

/Amy E. LaValle/ Lead Counsel for Petitioner Coalition for Affordable Drugs VII LLC